Is C2 p.Arg176Cys (c.526C>T) pathogenic?

C2 p.Arg176Cys (c.526C>T) is classified Uncertain significance in C2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-24). AlphaMissense: likely benign (0.287); Ultra-rare (popmax 0.0133%, afr).

How common is C2 p.Arg176Cys (c.526C>T) in the general population?

C2 p.Arg176Cys (c.526C>T) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about C2 p.Arg176Cys (c.526C>T)?

AlphaMissense predicts likely benign (score 0.287) — an in-silico prediction, not a clinical call.

C2 p.Arg176Cys

c.526C>T · rs143664003 · VCV1446034

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.287 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.287	likely benign
REVEL	0.479	indeterminate
SaProt	LLR -12.21	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.78, phastCons 0.99
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	27.9	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 0.0133% African / African-American · 10/74,944 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.000868% 14/1,613,080 alleles · ultra-rare exomes 11/1,460,832 · genomes 3/152,248 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,494
South Asian	0.0011%	91,090
European (non-Finnish)	0.000254%	393,349

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.Arg176Cys
Coding: c.526C>T
MANE Select: NM_000063
dbSNP: rs143664003
Type: single nucleotide variant
Location: chr6:31933693 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 176: the sushi 3 domain; a β-strand

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

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C2 p.Arg124Gln Uncertain significance ★★ ⚠ same type
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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-arg176cys (accessed [today's date]).

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