Is C1S p.Arg331His (c.992G>A) pathogenic?

C1S p.Arg331His (c.992G>A) is classified Uncertain significance in C1S (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.0754); Very rare (popmax 0.00535%, afr).

How common is C1S p.Arg331His (c.992G>A) in the general population?

C1S p.Arg331His (c.992G>A) is very rare (popmax 0.00535%, afr) (gnomAD).

What do computational predictors say about C1S p.Arg331His (c.992G>A)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

C1S p.Arg331His

c.992G>A · VCV3612061

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00535%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.006	GERP -3.4
Regional constraint	o/e 0.79	unconstrained · MANE · 3,608 bp · p 1.1e-05 · regional, not allelic
Overall
CADD	7.813	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 0.00535% African / African-American · 4/74,836 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000746% 12/1,609,436 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00535%	18,709
Remaining individualsnot grpmax-eligible	0.00481%	20,778
Admixed American	0.00167%	60,004
South Asian	0.0011%	90,996
European (non-Finnish)	0.000255%	391,939

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: C1S
Protein: p.Arg331His
Coding: c.992G>A
MANE Select: NM_001734
Type: single nucleotide variant
Location: chr12:7067043 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 331: a disulfide bond; the sushi 1 domain; a β-strand

Full C1S gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C1S p.Arg331Cys Uncertain significance ★★ ⚠ same residue
C1S p.Arg331Gly Uncertain significance ★ ⚠ same residue
C1S p.Arg331Leu Uncertain significance ★ ⚠ same residue
C1S p.Arg331Ser Uncertain significance ★ ⚠ same residue
C1S p.Arg523Ter Pathogenic ★★ same type
C1S c.1196-3C>T Uncertain significance ★★ same type
C1S c.717+5G>A Uncertain significance ★★ same type
C1S c.717+6T>A Uncertain significance ★★ 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/c1s-p-arg331his (accessed [today's date]).

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