Is C2CD3 p.Met331Thr (c.992T>C) pathogenic?

C2CD3 p.Met331Thr (c.992T>C) is classified Uncertain significance in C2CD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.7943); Absent from gnomAD v4.1; Associated with orofaciodigital syndrome type 14.

What condition is associated with C2CD3 p.Met331Thr (c.992T>C)?

C2CD3 p.Met331Thr (c.992T>C) is associated with orofaciodigital syndrome type 14 (ClinVar).

How common is C2CD3 p.Met331Thr (c.992T>C) in the general population?

C2CD3 p.Met331Thr (c.992T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C2CD3 p.Met331Thr (c.992T>C)?

AlphaMissense predicts likely pathogenic (score 0.7943) — an in-silico prediction, not a clinical call.

C2CD3 p.Met331Thr

c.992T>C · VCV4278317

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7943 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

orofaciodigital syndrome type 14

Computational evidence

Protein change
AlphaMissense	0.7943	likely pathogenic · top 10% in C2CD3
REVEL	0.315	indeterminate
SaProt	LLR -6.80	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	24.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: C2CD3
Protein: p.Met331Thr
Coding: c.992T>C
MANE Select: NM_001286577
Type: single nucleotide variant
Location: chr11:74133521 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65

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-met331thr (accessed [today's date]).

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