Is C2CD4A p.Ala192Glu (c.575C>A) pathogenic?

C2CD4A p.Ala192Glu (c.575C>A) is classified Uncertain significance in C2CD4A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-24). AlphaMissense: ambiguous (0.3676); Very rare (popmax 0.00154%, afr).

How common is C2CD4A p.Ala192Glu (c.575C>A) in the general population?

C2CD4A p.Ala192Glu (c.575C>A) is very rare (popmax 0.00154%, afr) (gnomAD).

What do computational predictors say about C2CD4A p.Ala192Glu (c.575C>A)?

AlphaMissense predicts ambiguous (score 0.3676) — an in-silico prediction, not a clinical call.

C2CD4A p.Ala192Glu

c.575C>A · VCV3262461

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3676 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00154%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3676	ambiguous
REVEL	0.045	moderately benign-leaning
SaProt	LLR -7.50	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.34	GERP 0.15
Regional constraint	o/e 1.06	unconstrained · MANE · 1,106 bp · p 0.13 · regional, not allelic
Overall
CADD	19.5	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 0.00154% African / African-American · 1/64,936 alleles

Overall 8.67e-05% 1/1,152,826 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: C2CD4A
Protein: p.Ala192Glu
Coding: c.575C>A
MANE Select: NM_207322
Type: single nucleotide variant
Location: chr15:62068188 (GRCh38)
Gene constraint: LOEUF 1.963 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.36

Full C2CD4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD4A p.Ala102Thr Uncertain significance ★ ⚠ same type
C2CD4A p.Ala160Thr Uncertain significance ★ ⚠ same type
C2CD4A p.Ala226Asp Uncertain significance ★ ⚠ same type
C2CD4A p.Ala318Thr Uncertain significance ★ ⚠ same type
C2CD4A p.Ala318Val Uncertain significance ★ ⚠ same type
C2CD4A p.Ala338Val Uncertain significance ★ ⚠ same type
C2CD4A p.Arg177Gly Uncertain significance ★ ⚠ same type
C2CD4A p.Arg180Cys 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/c2cd4a-p-ala192glu (accessed [today's date]).

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