Is C8A p.Tyr168His (c.502T>C) pathogenic?

C8A p.Tyr168His (c.502T>C) is classified Uncertain significance in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-20). AlphaMissense: likely pathogenic (0.6451); Ultra-rare (popmax 0.01%, nfe).

How common is C8A p.Tyr168His (c.502T>C) in the general population?

C8A p.Tyr168His (c.502T>C) is ultra-rare (popmax 0.01%, nfe) (gnomAD).

What do computational predictors say about C8A p.Tyr168His (c.502T>C)?

AlphaMissense predicts likely pathogenic (score 0.6451) — an in-silico prediction, not a clinical call.

C8A p.Tyr168His

c.502T>C · rs376646572 · VCV1949533

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6451 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6451	likely pathogenic
REVEL	0.523	indeterminate
SaProt	LLR -6.10	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	25.2	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 0.01% European (non-Finnish) · 118/1,179,744 alleles

Filtering AF 0.00851% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00795%

Overall 0.00781% 126/1,613,636 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.01%	9,998
African / African-American	0.00668%	14,979
Remaining individualsnot grpmax-eligible	0.0048%	20,823

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.Tyr168His
Coding: c.502T>C
MANE Select: NM_000562
dbSNP: rs376646572
Type: single nucleotide variant
Location: chr1:56881482 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 168: 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.Tyr168= 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
C8A p.Arg107Cys Uncertain significance ★★ ⚠ same type
C8A p.Arg196His 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-tyr168his (accessed [today's date]).

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