Is C8A p.Arg469Trp (c.1405C>T) pathogenic?

C8A p.Arg469Trp (c.1405C>T) is classified Uncertain significance in C8A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-11). AlphaMissense: likely benign (0.096); Ultra-rare (popmax 0.05%, amr).

How common is C8A p.Arg469Trp (c.1405C>T) in the general population?

C8A p.Arg469Trp (c.1405C>T) is ultra-rare (popmax 0.05%, amr) (gnomAD).

What do computational predictors say about C8A p.Arg469Trp (c.1405C>T)?

AlphaMissense predicts likely benign (score 0.096) — an in-silico prediction, not a clinical call.

C8A p.Arg469Trp

c.1405C>T · rs199713008 · VCV1440433

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.096 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.05%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.096	likely benign
REVEL	0.238	benign-leaning
SaProt	LLR -9.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -3.5
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.05% Admixed American · 30/60,028 alleles

Filtering AF 0.0359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0312%

Overall 0.00812% 131/1,614,158 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.05%	2,001
Middle Eastern	0.033%	3,031
East Asian	0.0245%	4,080
Remaining individualsnot grpmax-eligible	0.0176%	5,683
South Asian	0.00878%	11,386
African / African-American	0.00799%	12,511
European (non-Finnish)	0.00525%	19,032
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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.Arg469Trp
Coding: c.1405C>T
MANE Select: NM_000562
dbSNP: rs199713008
Type: single nucleotide variant
Location: chr1:56912427 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 469: a UniProt-annotated variant site (in c8d1); the macpf domain; an α-helix

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

Similar variants

C8A p.Arg469Gln Uncertain significance ★★ ⚠ same residue
C8A p.Arg469= 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

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-arg469trp (accessed [today's date]).

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