Is C8A p.Arg485Cys (c.1453C>T) pathogenic?

C8A p.Arg485Cys (c.1453C>T) is classified Uncertain significance in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-31). AlphaMissense: likely benign (0.3333); Very rare (popmax 0.00668%, eas).

How common is C8A p.Arg485Cys (c.1453C>T) in the general population?

C8A p.Arg485Cys (c.1453C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about C8A p.Arg485Cys (c.1453C>T)?

AlphaMissense predicts likely benign (score 0.3333) — an in-silico prediction, not a clinical call.

C8A p.Arg485Cys

c.1453C>T · rs370599466 · VCV1896814

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3333 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3333	likely benign
REVEL	0.389	indeterminate
SaProt	LLR -13.56	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 -0.78	GERP -3.2
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	20.7	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 0.00668% East Asian · 3/44,886 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00297% 48/1,614,078 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,962
Remaining individualsnot grpmax-eligible	0.0048%	20,827
Admixed American	0.00333%	30,004
European (non-Finnish)	0.00314%	31,893
African / African-American	0.00267%	37,469
Finnishnot grpmax-eligible	0.00156%	64,036

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.Arg485Cys
Coding: c.1453C>T
MANE Select: NM_000562
dbSNP: rs370599466
Type: single nucleotide variant
Location: chr1:56912475 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 485: a UniProt-annotated variant site (in c8d1); a UniProt-annotated variant site (in); the macpf domain; an α-helix

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

Similar variants

C8A p.Arg485= Benign/Likely benign ★★ same residue
C8A p.Arg485His Benign ★★ ⚠ same residue
C8A p.Arg485Leu 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

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-arg485cys (accessed [today's date]).

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