Is C8A p.Ala486Thr (c.1456G>A) pathogenic?

C8A p.Ala486Thr (c.1456G>A) is classified Uncertain significance in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-16). AlphaMissense: likely pathogenic (0.6871); Ultra-rare (popmax 0.0307%, sas).

How common is C8A p.Ala486Thr (c.1456G>A) in the general population?

C8A p.Ala486Thr (c.1456G>A) is ultra-rare (popmax 0.0307%, sas) (gnomAD).

What do computational predictors say about C8A p.Ala486Thr (c.1456G>A)?

AlphaMissense predicts likely pathogenic (score 0.6871) — an in-silico prediction, not a clinical call.

C8A p.Ala486Thr

c.1456G>A · rs772353770 · VCV2512557

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6871 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6871	likely pathogenic
REVEL	0.616	indeterminate
SaProt	LLR -12.31	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0307% South Asian · 28/91,080 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.00372% 60/1,614,198 alleles · ultra-rare exomes 57/1,461,870 · genomes 3/152,328 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0307%	3,253
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00246%	40,691
Remaining individualsnot grpmax-eligible	0.0016%	62,504
African / African-American	0.00133%	75,058

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.Ala486Thr
Coding: c.1456G>A
MANE Select: NM_000562
dbSNP: rs772353770
Type: single nucleotide variant
Location: chr1:56912478 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 486: 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.Ala486Ser Uncertain significance ★ ⚠ 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-ala486thr (accessed [today's date]).

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