Is C2CD4B p.Asp318Asn (c.952G>A) pathogenic?

C2CD4B p.Asp318Asn (c.952G>A) is classified Uncertain significance in C2CD4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: ambiguous (0.5205); Very rare (popmax 0.00169%, amr).

How common is C2CD4B p.Asp318Asn (c.952G>A) in the general population?

C2CD4B p.Asp318Asn (c.952G>A) is very rare (popmax 0.00169%, amr) (gnomAD).

What do computational predictors say about C2CD4B p.Asp318Asn (c.952G>A)?

AlphaMissense predicts ambiguous (score 0.5205) — an in-silico prediction, not a clinical call.

C2CD4B p.Asp318Asn

c.952G>A · VCV3993992

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5205 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Computational evidence

Protein change
AlphaMissense	0.5205	ambiguous
REVEL	0.511	indeterminate
SaProt	LLR -9.48	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 1,091 bp · p 0.0058 · regional, not allelic
Overall
CADD	27.2	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 0.00169% Admixed American · 1/59,112 alleles

Filtering AF 0.000766% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000607%

Overall 0.001% 16/1,600,648 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00169%	59,112
European (non-Finnish)	0.00128%	78,404

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: C2CD4B
Protein: p.Asp318Asn
Coding: c.952G>A
MANE Select: NM_001007595
Type: single nucleotide variant
Location: chr15:62164033 (GRCh38)
Structure: AlphaFold pLDDT 60.81
Residue 318: the c2 domain

Full C2CD4B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD4B p.Ala138Thr Uncertain significance ★ ⚠ same type
C2CD4B p.Ala190Gly Uncertain significance ★ ⚠ same type
C2CD4B p.Ala197Val Uncertain significance ★ ⚠ same type
C2CD4B p.Ala20Asp Uncertain significance ★ ⚠ same type
C2CD4B p.Ala231Pro Uncertain significance ★ ⚠ same type
C2CD4B p.Ala239Val Uncertain significance ★ ⚠ same type
C2CD4B p.Ala244Thr Uncertain significance ★ ⚠ same type
C2CD4B p.Ala244Val 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/c2cd4b-p-asp318asn (accessed [today's date]).

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