Is C2CD4B p.Asp316His (c.946G>C) pathogenic?

C2CD4B p.Asp316His (c.946G>C) is classified Uncertain significance in C2CD4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-01). AlphaMissense: likely benign (0.2262); Very rare (popmax 0.00453%, eas).

How common is C2CD4B p.Asp316His (c.946G>C) in the general population?

C2CD4B p.Asp316His (c.946G>C) is very rare (popmax 0.00453%, eas) (gnomAD).

What do computational predictors say about C2CD4B p.Asp316His (c.946G>C)?

AlphaMissense predicts likely benign (score 0.2262) — an in-silico prediction, not a clinical call.

C2CD4B p.Asp316His

c.946G>C · VCV3826308

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2262 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00453%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2262	likely benign
REVEL	0.348	indeterminate
SaProt	LLR -6.38	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 -2.3, phastCons 0.96
Regional constraint	o/e 1.11	unconstrained · MANE · 1,091 bp · p 0.0058 · regional, not allelic
Overall
CADD	23.6	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

Grpmax group 0.00453% East Asian · 2/44,192 alleles

Filtering AF 0.00075% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000281%

Overall 0.000125% 2/1,597,738 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: C2CD4B
Protein: p.Asp316His
Coding: c.946G>C
MANE Select: NM_001007595
Type: single nucleotide variant
Location: chr15:62164039 (GRCh38)
Structure: AlphaFold pLDDT 60.81
Residue 316: 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-asp316his (accessed [today's date]).

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