Is PROC p.Val11Met (c.31G>A) pathogenic?

PROC p.Val11Met (c.31G>A) is classified Uncertain significance in PROC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-03). AlphaMissense: likely benign (0.1011); Ultra-rare (popmax 0.0178%, eas).

How common is PROC p.Val11Met (c.31G>A) in the general population?

PROC p.Val11Met (c.31G>A) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about PROC p.Val11Met (c.31G>A)?

AlphaMissense predicts likely benign (score 0.1011) — an in-silico prediction, not a clinical call.

PROC p.Val11Met

c.31G>A · rs368493458 · VCV1339294

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1011 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1011	likely benign
REVEL	0.266	benign-leaning
SaProt	LLR -7.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	acceptor loss, 47 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -3.7	GERP -2.4
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	0.671	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0178% East Asian · 8/44,890 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00174% 28/1,613,716 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,611
African / African-American	0.004%	24,973
Remaining individualsnot grpmax-eligible	0.0016%	62,440
European (non-Finnish)	0.00136%	73,751

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.Val11Met
Coding: c.31G>A
MANE Select: NM_000312
dbSNP: rs368493458
Type: single nucleotide variant
Location: chr2:127419973 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB

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

Similar variants

PROC p.Ala178Pro Likely pathogenic ★★ ⚠ same type
PROC p.Ala309Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg199Ter Pathogenic ★★ same type
PROC p.Arg211Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg211Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg220Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg220Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg271Trp Pathogenic/Likely pathogenic ★★ same type

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-val11met (accessed [today's date]).

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