Is C2CD3 p.Arg577His (c.1730G>A) pathogenic?

C2CD3 p.Arg577His (c.1730G>A) is classified Likely pathogenic in C2CD3 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely benign (0.1117); Very rare (popmax 0.00167%, amr); Associated with orofaciodigital syndrome type 14.

What condition is associated with C2CD3 p.Arg577His (c.1730G>A)?

C2CD3 p.Arg577His (c.1730G>A) is associated with orofaciodigital syndrome type 14 (ClinVar).

How common is C2CD3 p.Arg577His (c.1730G>A) in the general population?

C2CD3 p.Arg577His (c.1730G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about C2CD3 p.Arg577His (c.1730G>A)?

AlphaMissense predicts likely benign (score 0.1117) — an in-silico prediction, not a clinical call.

C2CD3 p.Arg577His

c.1730G>A · rs755686768 · VCV2585641

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1117 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

orofaciodigital syndrome type 14

Computational evidence

Protein change
AlphaMissense	0.1117	likely benign ⚠ discordant with ClinVar
REVEL	0.156	moderately benign-leaning
SaProt	LLR -8.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.69	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.71	loss · gain 0.37 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	29.2	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 0.00167% Admixed American · 1/59,854 alleles

Filtering AF 0.000616% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000475%

Overall 0.000931% 15/1,611,260 alleles · very rare exomes 15/1,459,028 · genomes 0/152,232 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,854
African / African-American	0.00133%	74,964
European (non-Finnish)	0.0011%	90,606

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.Arg577His
Coding: c.1730G>A
MANE Select: NM_001286577
dbSNP: rs755686768
Type: single nucleotide variant
Location: chr11:74114384 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 577: the c2 1 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-arg577his (accessed [today's date]).

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