Is C8A p.Val167Met (c.499G>A) pathogenic?

C8A p.Val167Met (c.499G>A) is classified Uncertain significance in C8A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-04). AlphaMissense: ambiguous (0.3807); Ultra-rare (popmax 0.0507%, afr).

How common is C8A p.Val167Met (c.499G>A) in the general population?

C8A p.Val167Met (c.499G>A) is ultra-rare (popmax 0.0507%, afr) (gnomAD).

What do computational predictors say about C8A p.Val167Met (c.499G>A)?

AlphaMissense predicts ambiguous (score 0.3807) — an in-silico prediction, not a clinical call.

C8A p.Val167Met

c.499G>A · rs374176234 · VCV999601

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3807 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0507%, afr)

Computational evidence

Protein change
AlphaMissense	0.3807	ambiguous
REVEL	0.625	indeterminate
SaProt	LLR -8.83	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.1, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	25.0	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 0.0507% African / African-American · 38/74,892 alleles

Filtering AF 0.038% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0335%

Overall 0.00279% 45/1,613,662 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0507%	1,971
Admixed American	0.005%	19,988
Remaining individualsnot grpmax-eligible	0.0032%	31,238
European (non-Finnish)	0.00017%	589,873

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: C8A
Protein: p.Val167Met
Coding: c.499G>A
MANE Select: NM_000562
dbSNP: rs374176234
Type: single nucleotide variant
Location: chr1:56881479 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 167: a disulfide bond; a β-strand; the macpf domain

Full C8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C8A p.Arg424Ter Pathogenic ★★ same type
C8A p.Arg498Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Glu466Ter Pathogenic ★★ same type
C8A p.Tyr210Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Tyr384Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Arg107Cys Uncertain significance ★★ ⚠ same type
C8A p.Arg196His Uncertain significance ★★ ⚠ same type
C8A p.Arg207Gln 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/c8a-p-val167met (accessed [today's date]).

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