Is C2CD2 p.Ala136Gly (c.407C>G) pathogenic?

C2CD2 p.Ala136Gly (c.407C>G) is classified Uncertain significance in C2CD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-16). AlphaMissense: likely benign (0.1055); Absent from gnomAD v4.1.

How common is C2CD2 p.Ala136Gly (c.407C>G) in the general population?

C2CD2 p.Ala136Gly (c.407C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C2CD2 p.Ala136Gly (c.407C>G)?

AlphaMissense predicts likely benign (score 0.1055) — an in-silico prediction, not a clinical call.

C2CD2 p.Ala136Gly

c.407C>G · rs748403432 · VCV2289898

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1055 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1055	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -7.19	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 3.6	GERP -0.22, phastCons 0.65
Regional constraint	o/e 0.87	unconstrained · MANE · 65 kb · p 0.00014 · regional, not allelic
Overall
CADD	14.07	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: C2CD2
Protein: p.Ala136Gly
Coding: c.407C>G
MANE Select: NM_015500
dbSNP: rs748403432
Type: single nucleotide variant
Location: chr21:41922057 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.52
Residue 136: the smp-lbd domain

Full C2CD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD2 p.Pro104= Benign ★★ same type
C2CD2 p.Ala123Val Uncertain significance ★ ⚠ same type
C2CD2 p.Ala146Val Uncertain significance ★ ⚠ same type
C2CD2 p.Ala189Thr Uncertain significance ★ ⚠ same type
C2CD2 p.Ala207Val Uncertain significance ★ ⚠ same type
C2CD2 p.Ala345Val Uncertain significance ★ ⚠ same type
C2CD2 p.Ala466Thr Uncertain significance ★ ⚠ same type
C2CD2 p.Ala492Val 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/c2cd2-p-ala136gly (accessed [today's date]).

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