Is C2CD3 p.Val1641= (c.4923A>G) pathogenic?

C2CD3 p.Val1641= (c.4923A>G) is classified Benign in C2CD3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 47.4%, amr) — too common for a highly-penetrant pathogenic allele; Associated with orofaciodigital syndrome type 14.

What condition is associated with C2CD3 p.Val1641= (c.4923A>G)?

C2CD3 p.Val1641= (c.4923A>G) is associated with orofaciodigital syndrome type 14 (ClinVar).

C2CD3 p.Val1641=

Q: How common is C2CD3 p.Val1641= (c.4923A>G) in the general population?

C2CD3 p.Val1641= (c.4923A>G) is common (popmax 47.4%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4923A>G · rs4453265 · VCV1192631

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 47.4%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

orofaciodigital syndrome type 14

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.45	GERP 1.8, phastCons 0.14
Overall
CADD	6.083	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 47.4% Admixed American · 28,435/59,980 alleles

Filtering AF 46.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 46.8%

Overall 46.5% 750,556/1,613,406 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	58.5%	2
Admixed Americangrpmax	47.4%	2
East Asian	47.3%	2
South Asian	46.8%	2
European (non-Finnish)	46.1%	2
Remaining individualsnot grpmax-eligible	45.9%	2
Ashkenazi Jewishnot grpmax-eligible	45.8%	2
Middle Eastern	44.8%	2
Amishnot grpmax-eligible	44%	2
African / African-American	41.9%	2

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val1641=
Coding: c.4923A>G
MANE Select: NM_001286577
dbSNP: rs4453265
Type: single nucleotide variant
Location: chr11:74074281 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 1641: the c2 6 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-val1641 (accessed [today's date]).

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