Is C8B p.Gln319His (c.957G>C) pathogenic?

C8B p.Gln319His (c.957G>C) is classified Likely benign in C8B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-23). AlphaMissense: ambiguous (0.3687); Rare (popmax 0.477%, afr).

How common is C8B p.Gln319His (c.957G>C) in the general population?

C8B p.Gln319His (c.957G>C) is rare (popmax 0.477%, afr) (gnomAD).

What do computational predictors say about C8B p.Gln319His (c.957G>C)?

AlphaMissense predicts ambiguous (score 0.3687) — an in-silico prediction, not a clinical call.

C8B p.Gln319His

c.957G>C · rs146176997 · VCV1658665

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3687 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.477%, afr)

Computational evidence

Protein change
AlphaMissense	0.3687	ambiguous
REVEL	0.47	indeterminate
SaProt	LLR -7.48	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.35	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 1.8	GERP 2.1, phastCons 0.93
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	21.3	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 0.477% African / African-American · 358/75,062 alleles

Filtering AF 0.436% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.42%

Overall 0.0276% 445/1,614,178 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.477%	210
Admixed American	0.0583%	1,715
Remaining individualsnot grpmax-eligible	0.0448%	2,233
European (non-Finnish)	0.00195%	51,305
South Asian	0.0011%	91,086

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: C8B
Protein: p.Gln319His
Coding: c.957G>C
MANE Select: NM_000066
dbSNP: rs146176997
Type: single nucleotide variant
Location: chr1:56945969 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 319: a UniProt-annotated variant site (in c8d2); an α-helix; the macpf domain

Full C8B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C8B p.Arg284Ter Pathogenic ★★ same type
C8B p.Arg428Ter Pathogenic ★★ same type
C8B p.Cys508Ter Pathogenic/Likely pathogenic ★★ same type
C8B p.Gln91Ter Pathogenic/Likely pathogenic ★★ same type
C8B p.Trp9Ter Pathogenic ★★ same type
C8B p.Ala21Thr Uncertain significance ★★ ⚠ same type
C8B p.Ala446Val Uncertain significance ★★ ⚠ same type
C8B p.Ala461Ser 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/c8b-p-gln319his (accessed [today's date]).

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