Is C8A p.Tyr452Cys (c.1355A>G) pathogenic?

C8A p.Tyr452Cys (c.1355A>G) is classified Uncertain significance in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). AlphaMissense: ambiguous (0.5465); Very rare (popmax 0.000205%).

How common is C8A p.Tyr452Cys (c.1355A>G) in the general population?

C8A p.Tyr452Cys (c.1355A>G) is very rare (popmax 0.000205%) (gnomAD).

What do computational predictors say about C8A p.Tyr452Cys (c.1355A>G)?

AlphaMissense predicts ambiguous (score 0.5465) — an in-silico prediction, not a clinical call.

C8A p.Tyr452Cys

c.1355A>G · rs1037415351 · VCV2121700

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5465 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000205%)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5465	ambiguous
REVEL	0.709	pathogenic-leaning
SaProt	LLR -11.68	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	28.3	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 0.000205%

Overall 0.000205% 3/1,461,874 alleles · very rare

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.Tyr452Cys
Coding: c.1355A>G
MANE Select: NM_000562
dbSNP: rs1037415351
Type: single nucleotide variant
Location: chr1:56908088 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 452: 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.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
C8A p.Arg207Gln 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-tyr452cys (accessed [today's date]).

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