Is C2 p.Thr442Ala (c.1324A>G) pathogenic?

C2 p.Thr442Ala (c.1324A>G) is classified Conflicting classifications of pathogenicity in C2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-12). AlphaMissense: likely benign (0.0614); Rare (popmax 0.167%, afr).

How common is C2 p.Thr442Ala (c.1324A>G) in the general population?

C2 p.Thr442Ala (c.1324A>G) is rare (popmax 0.167%, afr) (gnomAD).

What do computational predictors say about C2 p.Thr442Ala (c.1324A>G)?

AlphaMissense predicts likely benign (score 0.0614) — an in-silico prediction, not a clinical call.

C2 p.Thr442Ala

c.1324A>G · rs140133472 · VCV1449986

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0614 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.167%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0614	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -4.78	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 -1.1	GERP -3.7
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	0.267	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 0.167% African / African-American · 125/75,048 alleles

Filtering AF 0.143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.134%

Overall 0.00806% 130/1,613,098 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.167%	600
Remaining individualsnot grpmax-eligible	0.0048%	20,833
Admixed American	0.00333%	30,015

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: C2
Protein: p.Thr442Ala
Coding: c.1324A>G
MANE Select: NM_000063
dbSNP: rs140133472
Type: single nucleotide variant
Location: chr6:31943063 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 442: the vwfa domain; an α-helix

Full C2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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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/c2-p-thr442ala (accessed [today's date]).

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