Is PROC p.Val26Met (c.76G>A) pathogenic?

PROC p.Val26Met (c.76G>A) is classified Likely pathogenic in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2019-02-01). AlphaMissense: likely benign (0.3205); Very rare (popmax 0.00446%, eas); Associated with Reduced protein C activity.

What condition is associated with PROC p.Val26Met (c.76G>A)?

PROC p.Val26Met (c.76G>A) is associated with Reduced protein C activity (ClinVar).

How common is PROC p.Val26Met (c.76G>A) in the general population?

PROC p.Val26Met (c.76G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about PROC p.Val26Met (c.76G>A)?

AlphaMissense predicts likely benign (score 0.3205) — an in-silico prediction, not a clinical call.

PROC p.Val26Met

c.76G>A · rs754243426 · VCV627133

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3205 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Reduced protein C activity

Computational evidence

Protein change
AlphaMissense	0.3205	likely benign ⚠ discordant with ClinVar
REVEL	0.867	moderately pathogenic-leaning
SaProt	LLR -9.17	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.43	acceptor gain · deltas
Pangolin	Δ0.43	gain · loss 0.24 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,878 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,613,744 alleles · very rare exomes 2/1,461,440 · genomes 0/152,304 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PROC
Protein: p.Val26Met
Coding: c.76G>A
MANE Select: NM_000312
dbSNP: rs754243426
Type: single nucleotide variant
Location: chr2:127421288 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 26: a β-strand

Full PROC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Reduced protein C activity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PROC p.Ala178Pro Likely pathogenic ★★ ⚠ same condition
PROC p.Cys147Tyr Likely pathogenic ★★ same condition
PROC c.797-2A>T Likely pathogenic ★ same condition
PROC p.Ser141Pro Likely pathogenic ★ same condition
PROC p.Thr340Lys Likely pathogenic ★ same condition
PROC p.Trp444Ter Likely pathogenic ★ same condition
PROC p.Ala388Val Conflicting classifications of pathogenicity ★ ⚠ same condition
PROC p.Leu303Arg Uncertain significance ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/proc-p-val26met (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown