Is PROC p.Ser292Arg (c.876C>G) pathogenic?

PROC p.Ser292Arg (c.876C>G) is classified Conflicting classifications of pathogenicity in PROC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-18). AlphaMissense: ambiguous (0.4031); Very rare (popmax 0.00667%, amr); Associated with Inborn genetic diseases.

What condition is associated with PROC p.Ser292Arg (c.876C>G)?

PROC p.Ser292Arg (c.876C>G) is associated with Inborn genetic diseases, thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Ser292Arg (c.876C>G) in the general population?

PROC p.Ser292Arg (c.876C>G) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about PROC p.Ser292Arg (c.876C>G)?

AlphaMissense predicts ambiguous (score 0.4031) — an in-silico prediction, not a clinical call.

PROC p.Ser292Arg

c.876C>G · rs1688669245 · VCV1150416

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4031 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4031	ambiguous
REVEL	0.545	indeterminate
SaProt	LLR -8.66	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.42	phastCons 0.21
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	15.76	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 0.00667% Admixed American · 4/60,012 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000434% 7/1,614,036 alleles · very rare exomes 3/1,461,820 · genomes 4/152,216 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,003
Remaining individualsnot grpmax-eligible	0.0048%	20,829

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.Ser292Arg
Coding: c.876C>G
MANE Select: NM_000312
dbSNP: rs1688669245
Type: single nucleotide variant
Location: chr2:127428436 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 292: the peptidase s1 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombophilia due to protein C deficiency, autosomal dominant

Similar variants

PROC p.Ser292Gly Uncertain significance ★ ⚠ same residue
PROC p.Ala309Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg199Ter Pathogenic ★★ same condition
PROC p.Arg211Gln Pathogenic/Likely 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

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-ser292arg (accessed [today's date]).

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