Is C8A p.Thr179Met (c.536C>T) pathogenic?

C8A p.Thr179Met (c.536C>T) is classified Uncertain significance in C8A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-09). AlphaMissense: likely benign (0.079); Ultra-rare (popmax 0.0909%, afr).

How common is C8A p.Thr179Met (c.536C>T) in the general population?

C8A p.Thr179Met (c.536C>T) is ultra-rare (popmax 0.0909%, afr) (gnomAD).

What do computational predictors say about C8A p.Thr179Met (c.536C>T)?

AlphaMissense predicts likely benign (score 0.079) — an in-silico prediction, not a clinical call.

C8A p.Thr179Met

c.536C>T · rs140970213 · VCV2082573

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.079 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0909%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.079	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -10.00	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -4
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	16.08	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 0.0909% African / African-American · 68/74,834 alleles

Filtering AF 0.0735% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0672%

Overall 0.00576% 93/1,613,566 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0909%	1,100
Middle Eastern	0.0165%	6,074
Remaining individualsnot grpmax-eligible	0.0048%	20,823
East Asian	0.00223%	44,886
South Asian	0.0022%	45,539
European (non-Finnish)	0.00153%	65,543

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.Thr179Met
Coding: c.536C>T
MANE Select: NM_000562
dbSNP: rs140970213
Type: single nucleotide variant
Location: chr1:56881516 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 179: a β-strand; the macpf domain

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

Similar variants

C8A p.Thr179Arg Uncertain significance ★ ⚠ same residue
C8A p.Thr179Lys Uncertain significance ★ ⚠ same residue
C8A p.Thr179= Likely benign ★ same residue
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

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-thr179met (accessed [today's date]).

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