Is C2CD3 p.Arg1248His (c.3743G>A) pathogenic?

C2CD3 p.Arg1248His (c.3743G>A) is classified Conflicting classifications of pathogenicity in C2CD3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1014); Ultra-rare (popmax 0.0329%, mid); Associated with orofaciodigital syndrome type 14.

What condition is associated with C2CD3 p.Arg1248His (c.3743G>A)?

C2CD3 p.Arg1248His (c.3743G>A) is associated with orofaciodigital syndrome type 14 (ClinVar).

How common is C2CD3 p.Arg1248His (c.3743G>A) in the general population?

C2CD3 p.Arg1248His (c.3743G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about C2CD3 p.Arg1248His (c.3743G>A)?

AlphaMissense predicts likely benign (score 0.1014) — an in-silico prediction, not a clinical call.

C2CD3 p.Arg1248His

c.3743G>A · rs750302216 · VCV2178923

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1014 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

orofaciodigital syndrome type 14

Computational evidence

Protein change
AlphaMissense	0.1014	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -6.90	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 4.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	22.6	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00291% 47/1,613,952 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Remaining individualsnot grpmax-eligible	0.0128%	7,810
European (non-Finnish)	0.00297%	33,715
African / African-American	0.00134%	74,898
South Asian	0.0011%	91,072

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: C2CD3
Protein: p.Arg1248His
Coding: c.3743G>A
MANE Select: NM_001286577
dbSNP: rs750302216
Type: single nucleotide variant
Location: chr11:74085785 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 1248: the c2 4 domain

Full C2CD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

orofaciodigital syndrome type 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C2CD3 p.Arg1248Cys Uncertain significance ★★ ⚠ same residue
C2CD3 c.3911-2A>T Pathogenic/Likely pathogenic ★★ same condition
C2CD3 p.Arg621Ter Pathogenic/Likely pathogenic ★★ same condition
C2CD3 p.Arg666Ter Pathogenic ★★ same condition
C2CD3 c.5495+4A>G Uncertain significance ★★ same condition
C2CD3 c.5882-332A>G Uncertain significance ★★ same condition
C2CD3 p.Arg1061Thr Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1553Gln Uncertain significance ★★ ⚠ same condition

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/c2cd3-p-arg1248his (accessed [today's date]).

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