Is C8A p.Arg480Cys (c.1438C>T) pathogenic?

C8A p.Arg480Cys (c.1438C>T) is classified Uncertain significance in C8A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.2541); Very rare (popmax 0.00668%, eas).

How common is C8A p.Arg480Cys (c.1438C>T) in the general population?

C8A p.Arg480Cys (c.1438C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about C8A p.Arg480Cys (c.1438C>T)?

AlphaMissense predicts likely benign (score 0.2541) — an in-silico prediction, not a clinical call.

C8A p.Arg480Cys

c.1438C>T · rs774470099 · VCV1414473

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2541 · 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	0.2541	likely benign
REVEL	0.564	indeterminate
SaProt	LLR -10.88	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 -0.021	GERP -0.74, phastCons 0.002
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	19.62	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 · 3/44,880 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000991% 16/1,614,220 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,960
Admixed American	0.005%	20,010
Remaining individualsnot grpmax-eligible	0.0032%	31,256
South Asian	0.0011%	91,084
European (non-Finnish)	0.000593%	168,576

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.Arg480Cys
Coding: c.1438C>T
MANE Select: NM_000562
dbSNP: rs774470099
Type: single nucleotide variant
Location: chr1:56912460 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 480: 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.Arg480His Uncertain significance ★★ ⚠ same residue
C8A p.Arg480= 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-arg480cys (accessed [today's date]).

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