Is C2CD2 p.Ala123Val (c.368C>T) pathogenic?

C2CD2 p.Ala123Val (c.368C>T) is classified Uncertain significance in C2CD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). AlphaMissense: likely benign (0.0978); Ultra-rare (popmax 0.026%, afr).

How common is C2CD2 p.Ala123Val (c.368C>T) in the general population?

C2CD2 p.Ala123Val (c.368C>T) is ultra-rare (popmax 0.026%, afr) (gnomAD).

What do computational predictors say about C2CD2 p.Ala123Val (c.368C>T)?

AlphaMissense predicts likely benign (score 0.0978) — an in-silico prediction, not a clinical call.

C2CD2 p.Ala123Val

c.368C>T · rs201798564 · VCV2235571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0978 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.026%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0978	likely benign
REVEL	0.027	moderately benign-leaning
SaProt	LLR -2.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.39	donor gain · deltas
Pangolin	Δ0.27	gain · loss 0.17 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.8	GERP -0.63, phastCons 0.94
Regional constraint	o/e 0.87	unconstrained · MANE · 65 kb · p 0.00014 · regional, not allelic
Overall
CADD	18.56	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

Grpmax group 0.026% African / African-American · 19/73,022 alleles

Filtering AF 0.017% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0141%

Overall 0.00239% 37/1,549,244 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.026%	3,843
East Asian	0.0244%	4,092
Remaining individualsnot grpmax-eligible	0.00334%	29,961
South Asian	0.00119%	83,942
European (non-Finnish)	0.000436%	229,358

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: C2CD2
Protein: p.Ala123Val
Coding: c.368C>T
MANE Select: NM_015500
dbSNP: rs201798564
Type: single nucleotide variant
Location: chr21:41942157 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.52
Residue 123: 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.Ala136Gly 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-ala123val (accessed [today's date]).

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