Is C1S p.Ala231= (c.693G>T) pathogenic?

C1S p.Ala231= (c.693G>T) is classified Likely benign in C1S (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-11). Ultra-rare (popmax 0.0454%, afr).

How common is C1S p.Ala231= (c.693G>T) in the general population?

C1S p.Ala231= (c.693G>T) is ultra-rare (popmax 0.0454%, afr) (gnomAD).

C1S p.Ala231=

c.693G>T · rs374425292 · VCV2190705

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0454%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.32	GERP -3
Overall
CADD	6.208	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0454% African / African-American · 34/74,898 alleles

Filtering AF 0.0334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0292%

Overall 0.00229% 37/1,613,726 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0454%	2,203
Remaining individualsnot grpmax-eligible	0.0032%	31,234
Admixed American	0.00167%	60,002

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.Ala231=
Coding: c.693G>T
MANE Select: NM_001734
dbSNP: rs374425292
Type: single nucleotide variant
Location: chr12:7065275 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 231: the cub 2 domain

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

Similar variants

C1S p.Ala231Val Uncertain significance ★★ ⚠ same residue
C1S p.Ala231Gly 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
C1S p.Ala227Val Uncertain significance ★★ ⚠ same type
C1S p.Ala584Val 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-ala231 (accessed [today's date]).

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