Is C2CD3 p.Ala53Glu (c.158C>A) pathogenic?

C2CD3 p.Ala53Glu (c.158C>A) is classified Uncertain significance in C2CD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). AlphaMissense: likely benign (0.2095); Absent from gnomAD v4.1.

How common is C2CD3 p.Ala53Glu (c.158C>A) in the general population?

C2CD3 p.Ala53Glu (c.158C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C2CD3 p.Ala53Glu (c.158C>A)?

AlphaMissense predicts likely benign (score 0.2095) — an in-silico prediction, not a clinical call.

C2CD3 p.Ala53Glu

c.158C>A · rs2135578312 · VCV1424243

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2095 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2095	likely benign
REVEL	0.249	benign-leaning
SaProt	LLR -1.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: C2CD3
Protein: p.Ala53Glu
Coding: c.158C>A
MANE Select: NM_001286577
dbSNP: rs2135578312
Type: single nucleotide variant
Location: chr11:74168511 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65

Full C2CD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD3 c.3911-2A>T Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Arg621Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Arg666Ter Pathogenic ★★ same type
C2CD3 p.Arg768Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Tyr173Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 c.2085+5G>A Uncertain significance ★★ same type
C2CD3 c.4951+6C>T Uncertain significance ★★ same type
C2CD3 c.5495+4A>G 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/c2cd3-p-ala53glu (accessed [today's date]).

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