Is PROC p.Val76Met (c.226G>A) pathogenic?

PROC p.Val76Met (c.226G>A) is classified Pathogenic/Likely pathogenic in PROC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-06-10). AlphaMissense: likely benign (0.0898); Ultra-rare (popmax 0.0168%, nfe); Associated with Abnormal thrombosis.

What condition is associated with PROC p.Val76Met (c.226G>A)?

PROC p.Val76Met (c.226G>A) is associated with Abnormal thrombosis, cerebral palsy, thrombophilia due to protein C deficiency, autosomal recessive (ClinVar).

How common is PROC p.Val76Met (c.226G>A) in the general population?

PROC p.Val76Met (c.226G>A) is ultra-rare (popmax 0.0168%, nfe) (gnomAD).

What do computational predictors say about PROC p.Val76Met (c.226G>A)?

AlphaMissense predicts likely benign (score 0.0898) — an in-silico prediction, not a clinical call.

PROC p.Val76Met

c.226G>A · rs121918149 · VCV665

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0898 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Abnormal thrombosis

Computational evidence

Protein change
AlphaMissense	0.0898	likely benign ⚠ discordant with ClinVar
REVEL	0.651	pathogenic-leaning
SaProt	LLR -5.67	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	phastCons 0.98
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	20.7	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 0.0168% European (non-Finnish) · 198/1,179,968 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0141%

Overall 0.0134% 217/1,613,810 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0304%	3,288
European (non-Finnish)grpmax	0.0168%	5,959

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val76Met
Coding: c.226G>A
MANE Select: NM_000312
dbSNP: rs121918149
Type: single nucleotide variant
Location: chr2:127421438 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 76: an α-helix; a UniProt-annotated variant site (in thph3; vermont-1); the gla domain

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

Disease context

Abnormal thrombosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cerebral palsy thrombophilia due to protein C deficiency, autosomal recessive

Similar variants

PROC p.Ala309Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg199Ter Pathogenic ★★ same condition
PROC p.Arg211Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg220Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg220Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg271Trp Pathogenic/Likely pathogenic ★★ same condition
PROC p.Arg42Cys Pathogenic/Likely pathogenic ★★ same condition
PROC p.Arg57Trp Pathogenic/Likely pathogenic ★★ ⚠ 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-val76met (accessed [today's date]).

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