Is C2CD3 p.Arg1248Cys (c.3742C>T) pathogenic?

C2CD3 p.Arg1248Cys (c.3742C>T) is classified Uncertain significance in C2CD3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-15). AlphaMissense: likely benign (0.1379); Ultra-rare (popmax 0.0432%, nfe); Associated with Inborn genetic diseases.

What condition is associated with C2CD3 p.Arg1248Cys (c.3742C>T)?

C2CD3 p.Arg1248Cys (c.3742C>T) is associated with Inborn genetic diseases, orofaciodigital syndrome type 14 (ClinVar).

How common is C2CD3 p.Arg1248Cys (c.3742C>T) in the general population?

C2CD3 p.Arg1248Cys (c.3742C>T) is ultra-rare (popmax 0.0432%, nfe) (gnomAD).

What do computational predictors say about C2CD3 p.Arg1248Cys (c.3742C>T)?

AlphaMissense predicts likely benign (score 0.1379) — an in-silico prediction, not a clinical call.

C2CD3 p.Arg1248Cys

c.3742C>T · rs139665472 · VCV1404581

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1379 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0432%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1379	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -7.73	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	31.0	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 0.0432% European (non-Finnish) · 510/1,180,026 alleles

Filtering AF 0.0401% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0388%

Overall 0.0361% 582/1,614,138 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0432%	2,314
Remaining individualsnot grpmax-eligible	0.0416%	2,404
Middle Eastern	0.033%	3,031
Admixed American	0.03%	3,335
South Asian	0.0198%	5,059
African / African-American	0.00933%	10,720
Finnishnot grpmax-eligible	0.00156%	64,020

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.Arg1248Cys
Coding: c.3742C>T
MANE Select: NM_001286577
dbSNP: rs139665472
Type: single nucleotide variant
Location: chr11:74085786 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: orofaciodigital syndrome type 14

Similar variants

C2CD3 p.Arg1248His Conflicting classifications of pathogenicity ★ ⚠ 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.2085+5G>A Uncertain significance ★★ same condition
C2CD3 c.4951+6C>T Uncertain significance ★★ same condition
C2CD3 c.5495+4A>G Uncertain significance ★★ same condition
C2CD3 c.5882-332A>G 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-arg1248cys (accessed [today's date]).

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