Is C1S p.Ala11Ser (c.31G>T) pathogenic?

C1S p.Ala11Ser (c.31G>T) is classified Likely benign in C1S (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-07). AlphaMissense: likely benign (0.0817); Rare (popmax 0.108%, afr).

How common is C1S p.Ala11Ser (c.31G>T) in the general population?

C1S p.Ala11Ser (c.31G>T) is rare (popmax 0.108%, afr) (gnomAD).

What do computational predictors say about C1S p.Ala11Ser (c.31G>T)?

AlphaMissense predicts likely benign (score 0.0817) — an in-silico prediction, not a clinical call.

C1S p.Ala11Ser

c.31G>T · rs375886488 · VCV1155296

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0817 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.108%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0817	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -5.69	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 2.8	GERP -3.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 4,638 bp · p 0.66 · regional, not allelic
Overall
CADD	15.91	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 0.108% African / African-American · 81/74,968 alleles

Filtering AF 0.089% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0821%

Overall 0.00775% 125/1,613,290 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.108%	926
Remaining individualsnot grpmax-eligible	0.0144%	6,936
European (non-Finnish)	0.00288%	34,706
Admixed American	0.00167%	60,014

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.Ala11Ser
Coding: c.31G>T
MANE Select: NM_001734
dbSNP: rs375886488
Type: single nucleotide variant
Location: chr12:7062500 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB

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

Similar variants

C1S p.Ala11Val Conflicting classifications of pathogenicity ★ ⚠ same residue
C1S p.Ala11Leu 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.Ala231Val 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-ala11ser (accessed [today's date]).

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