rs6235 — PCSK1 PCSK1 S690T (Ser690Thr)

Missense variant encoding the Ser690Thr substitution in the C-terminal domain of prohormone convertase 1/3 (PC1/3); paired with rs6234 (Q665E) in near-complete LD to form the Q665E-S690T haplotype that reduces PC1/3 enzymatic efficiency, impairing proinsulin-to-insulin conversion and POMC processing to satiety peptides, and conferring modest obesity risk

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PCSK1 S690T — The Prohormone Scissor's Hidden Flaw

Every time your pancreatic beta cells sense rising blood glucose, they do not release insulin directly — they release proinsulin11 proinsulin
An inactive precursor of insulin that must be cleaved at two sites to release active insulin and C-peptide; elevated circulating proinsulin is a clinical marker of impaired beta-cell processing, a folded precursor that needs enzymatic cutting to become active. The enzyme responsible for most of that cleavage is prohormone convertase 1/3 (PC1/3), encoded by the PCSK1 gene on chromosome 5. PC1/3 also cleaves pro-opiomelanocortin (POMC) into the satiety peptide α-MSH in hypothalamic neurons, and proglucagon into GLP-1 in gut enteroendocrine cells. A single enzyme sits at the convergence of insulin release, appetite regulation, and incretin signaling.

rs6235 causes a serine-to-threonine substitution at position 690 of PC1/3 (S690T). It almost always travels alongside rs6234 (Q665E) in the same haplotype — in European populations the two variants are in near-complete linkage disequilibrium. Together they define the Q665E-S690T haplotype, which is the functional basis for the common PCSK1 obesity association22 common PCSK1 obesity association
Benzinou M et al. Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat Genet, 2008 first demonstrated in 13,659 Europeans across eight cohorts.

The Mechanism

The S690T substitution lies within the C-terminal propeptide region of PC1/3. This domain acts as an intramolecular chaperone that guides proper folding of the mature enzyme after synthesis — it is cleaved off as part of the activation process, but its sequence influences how efficiently the enzyme assembles. The Q665E-S690T haplotype together alters this C-terminal region, reducing overall catalytic efficiency without abolishing enzyme function. Functional studies by Mbikay et al. 201133 Mbikay et al. 2011
Effects of rs6234/rs6235 and rs6232/rs6234/rs6235 PCSK1 single-nucleotide polymorphism clusters on proprotein convertase 1/3 biosynthesis and activity. Mol Genet Metab, 2011 showed that the double-variant isoform undergoes increased C-terminal proteolytic processing relative to the wild-type form, consistent with impaired folding — and proposed that this creates a subtle chronic deficit in PC1/3 enzymatic activity in endocrine and neuroendocrine cells.

The downstream consequences propagate through three pathways: slower proinsulin-to-insulin conversion (raising the circulating proinsulin fraction), reduced POMC cleavage into α-MSH (partially blunting melanocortin-4 receptor-mediated satiety signaling), and potentially impaired proglucagon processing to GLP-1 (modifying incretin-amplified insulin release after meals). None of these effects is catastrophic alone, but their convergence on energy balance creates a consistent metabolic tilt.

The Evidence

The founding population-genetic study44 population-genetic study
Benzinou M et al. Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat Genet, 2008 established the rs6234-rs6235 haplotype as a robust obesity locus (p = 2.31 × 10⁻¹²) and confirmed functional PC1/3 impairment in cell-based assays. The largest meta-analysis to date, Nead et al. 201555 Nead et al. 2015
Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331,175 individuals. Hum Mol Genet, 2015, quantified the effect: OR = 1.07 (95% CI 1.04–1.10) per rs6235 G allele for obesity, and a BMI increase of 0.02 per allele (p = 5.57 × 10⁻⁴). These are modest per-allele effects consistent with the polygenic architecture of common obesity, but they replicate at genome-wide significance across diverse ancestries.

Critically, the metabolic consequence was directly measured by Heni et al. 201066 Heni et al. 2010
Association of obesity risk SNPs in PCSK1 with insulin sensitivity and proinsulin conversion. BMC Med Genet, 2010: in 1,498 German subjects, each rs6235 G allele was associated with 8% higher proinsulin area under the curve (AUC) and a significantly elevated proinsulin-to-insulin ratio (p ≤ 0.009). This is in vivo biochemical evidence that S690T reduces prohormone processing efficiency, not merely a statistical association with BMI.

The evidence level is rated strong: there is consistent replication across multiple large cohorts and meta-analyses (total n > 300,000), clear biological mechanism, and direct in vivo biomarker confirmation. Effect sizes are modest (OR 1.07 per allele), but the molecular chain from variant to protein change to proinsulin accumulation to obesity risk is more complete than most common GWAS loci.

Practical Actions

The primary actionable lever for G-allele carriers is glycemic load management. Each postprandial glucose peak triggers a pulse of proinsulin secretion from beta cells — in carriers with reduced PC1/3 efficiency, those pulses are converted to active insulin less completely, leaving more proinsulin in circulation. Reducing the amplitude of postprandial glucose excursions reduces the secretory burden on an already less-efficient processing system. Fasting proinsulin and the proinsulin:C-peptide ratio are direct biomarkers for PC1/3 processing efficiency — they detect impairment before HbA1c rises and are available through specialist endocrinology labs.

Protein intake supports satiety through pathways that bypass PC1/3: peptide YY (PYY), cholecystokinin (CCK), and peripheral GLP-1 receptor activation do not require the PC1/3-dependent α-MSH pathway, and can partially compensate for reduced melanocortin-mediated satiety.

Interactions

rs6235 is essentially always co-inherited with rs6234 (Q665E) in European populations — the two define the Q665E-S690T haplotype. rs10515237, an intronic PCSK1 variant in strong LD with this haplotype (r² ≈ 0.84), is the tag SNP for this locus on the HapMap/OmniExpress arrays. rs6232 (N221D, encoded by a separate PCSK1 variant with MAF ~6%) independently reduces PC1/3 catalytic activity at the active site and shows an additive effect with the rs6234/rs6235 haplotype — carriers of both face compound PC1/3 impairment. The MC4R variant rs17782313, downstream of PC1/3 in the POMC→α-MSH→MC4R satiety axis, would compound the satiety impairment created by reduced POMC processing.

Nutrient Interactions

protein increased_need
simple carbohydrates altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal PC1/3 Processing Normal

Common genotype with normal prohormone convertase 1/3 S690 activity

You carry two copies of the C allele at rs6235, the common reference genotype found in approximately 53% of people globally. The S690T substitution is absent: your PC1/3 enzyme retains the wild-type serine at position 690, and the Q665E-S690T haplotype that reduces C-terminal folding efficiency is not present. Proinsulin-to-insulin conversion, POMC processing to α-MSH, and proglucagon processing to GLP-1 all proceed at normal efficiency. The CC genotype carries reference-level obesity risk at this locus.

CG Reduced PC1/3 Processing Intermediate

One S690T allele modestly reduces prohormone convertase efficiency, mildly elevating proinsulin and blunting satiety signaling

The S690T change in the C-terminal propeptide domain of PC1/3 reduces the efficiency of the enzyme's self-folding process. Heterozygous carriers have one normal copy and one reduced-efficiency copy of PC1/3, resulting in partial impairment rather than complete loss-of-function. The measurable consequence in vivo is an elevated proinsulin fraction: beta cells secrete proinsulin in the normal amount, but conversion to active insulin is slower, leaving more proinsulin circulating after meals. Chronically elevated proinsulin is a low-grade marker of beta-cell stress and an independent predictor of type 2 diabetes risk. The melanocortin satiety pathway is also partially affected: reduced POMC cleavage to α-MSH means the MC4R receptor receives a weaker signal after meals, potentially contributing to a slightly higher satiety threshold.

GG Low PC1/3 Processing Reduced

Two S690T alleles substantially reduce prohormone convertase efficiency, raising proinsulin, impairing satiety signaling, and increasing obesity and diabetes risk

GG homozygosity means both PC1/3 alleles carry the S690T change, producing the most complete version of the common Q665E-S690T haplotype's enzymatic impairment. Proinsulin accumulation is highest in this genotype. Chronically elevated proinsulin — even within the nominal "normal" range — is an established independent predictor of cardiovascular events and type 2 diabetes in large prospective cohorts; it reflects beta-cell secretory inefficiency that precedes detectable HbA1c elevation by years.

In the brain, reduced PC1/3 activity impairs POMC cleavage into α-MSH in hypothalamic arcuate neurons. α-MSH is the primary endogenous agonist of the melanocortin-4 receptor (MC4R), which is the principal satiety receptor in the hypothalamus. Blunted α-MSH generation means MC4R receives a weaker stop-eating signal after meals. In the gut, impaired proglucagon processing to GLP-1 in enteroendocrine L cells reduces the incretin amplification of postprandial insulin release.

Biallelic loss-of-function PCSK1 mutations cause severe early-onset obesity, malabsorptive diarrhea, and hypogonadotropic hypogonadism — demonstrating what complete PC1/3 absence produces. The GG genotype at rs6235 is a mild version of the same directional biology, not a severe disease state, but the mechanistic continuum is the same.