Is C8A p.Arg59Gln (c.176G>A) pathogenic?

C8A p.Arg59Gln (c.176G>A) is classified Benign in C8A (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-03). AlphaMissense: likely benign (0.1628); Rare (popmax 0.678%, sas).

How common is C8A p.Arg59Gln (c.176G>A) in the general population?

C8A p.Arg59Gln (c.176G>A) is rare (popmax 0.678%, sas) (gnomAD).

What do computational predictors say about C8A p.Arg59Gln (c.176G>A)?

AlphaMissense predicts likely benign (score 0.1628) — an in-silico prediction, not a clinical call.

C8A p.Arg59Gln

c.176G>A · rs369702409 · VCV1666981

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1628 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.678%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1628	likely benign
REVEL	0.454	indeterminate
SaProt	LLR -12.12	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	28.4	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 0.678% South Asian · 617/91,048 alleles

Filtering AF 0.633% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.616%

Overall 0.0419% 676/1,613,528 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.678%	148
Remaining individualsnot grpmax-eligible	0.0432%	2,313
Middle Eastern	0.0166%	6,018
Finnishnot grpmax-eligible	0.00469%	21,324
African / African-American	0.004%	25,001
Admixed American	0.00334%	29,984
European (non-Finnish)	0.00195%	51,293

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.Arg59Gln
Coding: c.176G>A
MANE Select: NM_000562
dbSNP: rs369702409
Type: single nucleotide variant
Location: chr1:56874953 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 59: a disulfide bond; a β-strand; the tsp type-1 1 domain

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

Similar variants

C8A p.Arg59Ter Conflicting classifications of pathogenicity ★ 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-arg59gln (accessed [today's date]).

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