Is C2CD4B p.Gly249Ser (c.745G>A) pathogenic?

C2CD4B p.Gly249Ser (c.745G>A) is classified Uncertain significance in C2CD4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely benign (0.1746); Ultra-rare (popmax 0.0284%, sas).

How common is C2CD4B p.Gly249Ser (c.745G>A) in the general population?

C2CD4B p.Gly249Ser (c.745G>A) is ultra-rare (popmax 0.0284%, sas) (gnomAD).

What do computational predictors say about C2CD4B p.Gly249Ser (c.745G>A)?

AlphaMissense predicts likely benign (score 0.1746) — an in-silico prediction, not a clinical call.

C2CD4B p.Gly249Ser

c.745G>A · VCV4217288

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1746 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0284%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1746	likely benign
REVEL	0.273	benign-leaning
SaProt	LLR -8.09	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 2.4	GERP -0.95, phastCons 0.016
Regional constraint	o/e 1.11	unconstrained · MANE · 1,091 bp · p 0.0058 · regional, not allelic
Overall
CADD	23.2	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 0.0284% South Asian · 21/73,906 alleles

Filtering AF 0.019% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0159%

Overall 0.00172% 25/1,453,084 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0284%	3,519
Middle Eastern	0.0233%	4,286
European (non-Finnish)	0.00027%	370,490

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.Gly249Ser
Coding: c.745G>A
MANE Select: NM_001007595
Type: single nucleotide variant
Location: chr15:62164240 (GRCh38)
Structure: AlphaFold pLDDT 60.81
Residue 249: 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-gly249ser (accessed [today's date]).

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