Is C8A p.Pro475Arg (c.1424C>G) pathogenic?

C8A p.Pro475Arg (c.1424C>G) is classified Conflicting classifications of pathogenicity in C8A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0808); Rare (popmax 0.851%, afr).

How common is C8A p.Pro475Arg (c.1424C>G) in the general population?

C8A p.Pro475Arg (c.1424C>G) is rare (popmax 0.851%, afr) (gnomAD).

What do computational predictors say about C8A p.Pro475Arg (c.1424C>G)?

AlphaMissense predicts likely benign (score 0.0808) — an in-silico prediction, not a clinical call.

C8A p.Pro475Arg

c.1424C>G · rs143256214 · VCV714070

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0808 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.851%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0808	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -4.56	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.54	GERP -3.2
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	8.94	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 0.851% African / African-American · 639/75,060 alleles

Filtering AF 0.797% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.775%

Overall 0.047% 759/1,614,216 alleles · rare exomes 367/1,461,874 · genomes 392/152,342 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.851%	117
Admixed American	0.0833%	1,201
Remaining individualsnot grpmax-eligible	0.0784%	1,276
European (non-Finnish)	0.00178%	56,192

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.Pro475Arg
Coding: c.1424C>G
MANE Select: NM_000562
dbSNP: rs143256214
Type: single nucleotide variant
Location: chr1:56912446 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 475: a UniProt-annotated variant site (in c8d1); the macpf domain

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

Similar variants

C8A p.Pro475Leu Uncertain significance ★ ⚠ same residue
C8A p.Pro475fs Pathogenic ★ 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

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-pro475arg (accessed [today's date]).

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