Is C2CD3 p.Lys835Ile (c.2504A>T) pathogenic?

C2CD3 p.Lys835Ile (c.2504A>T) is classified Uncertain significance in C2CD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.8743); Ultra-rare (popmax 0.015%, amr); Associated with orofaciodigital syndrome type 14.

What condition is associated with C2CD3 p.Lys835Ile (c.2504A>T)?

C2CD3 p.Lys835Ile (c.2504A>T) is associated with orofaciodigital syndrome type 14 (ClinVar).

How common is C2CD3 p.Lys835Ile (c.2504A>T) in the general population?

C2CD3 p.Lys835Ile (c.2504A>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about C2CD3 p.Lys835Ile (c.2504A>T)?

AlphaMissense predicts likely pathogenic (score 0.8743) — an in-silico prediction, not a clinical call.

C2CD3 p.Lys835Ile

c.2504A>T · rs779366546 · VCV1311851

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8743 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

orofaciodigital syndrome type 14

Computational evidence

Protein change
AlphaMissense	0.8743	likely pathogenic · top 7% in C2CD3
REVEL	0.821	moderately pathogenic-leaning
SaProt	LLR -9.04	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	26.6	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 0.015% Admixed American · 9/60,014 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.000558% 9/1,614,090 alleles · ultra-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: C2CD3
Protein: p.Lys835Ile
Coding: c.2504A>T
MANE Select: NM_001286577
dbSNP: rs779366546
Type: single nucleotide variant
Location: chr11:74103207 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 835: the c2 2 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 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.Arg1248Cys 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-lys835ile (accessed [today's date]).

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