Is C2CD4A p.Gln322Arg (c.965A>G) pathogenic?

C2CD4A p.Gln322Arg (c.965A>G) is classified Uncertain significance in C2CD4A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.0942); Very rare (popmax 0.000259%, nfe).

How common is C2CD4A p.Gln322Arg (c.965A>G) in the general population?

C2CD4A p.Gln322Arg (c.965A>G) is very rare (popmax 0.000259%, nfe) (gnomAD).

What do computational predictors say about C2CD4A p.Gln322Arg (c.965A>G)?

AlphaMissense predicts likely benign (score 0.0942) — an in-silico prediction, not a clinical call.

C2CD4A p.Gln322Arg

c.965A>G · VCV3993982

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000259%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0942	likely benign
REVEL	0.388	indeterminate
SaProt	LLR -6.24	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -1.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,106 bp · p 0.13 · regional, not allelic
Overall
CADD	24.0	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 0.000259% European (non-Finnish) · 3/1,159,846 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000211% 3/1,421,286 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.Gln322Arg
Coding: c.965A>G
MANE Select: NM_207322
Type: single nucleotide variant
Location: chr15:62068578 (GRCh38)
Gene constraint: LOEUF 1.963 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.36
Residue 322: the c2 domain

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.Ala192Glu 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

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-gln322arg (accessed [today's date]).

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