Is C2CD3 p.Pro655Gln (c.1964C>A) pathogenic?

C2CD3 p.Pro655Gln (c.1964C>A) is classified Conflicting classifications of pathogenicity in C2CD3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-02). AlphaMissense: likely pathogenic (0.7474); Rare (popmax 0.54%, sas).

How common is C2CD3 p.Pro655Gln (c.1964C>A) in the general population?

C2CD3 p.Pro655Gln (c.1964C>A) is rare (popmax 0.54%, sas) (gnomAD).

What do computational predictors say about C2CD3 p.Pro655Gln (c.1964C>A)?

AlphaMissense predicts likely pathogenic (score 0.7474) — an in-silico prediction, not a clinical call.

C2CD3 p.Pro655Gln

c.1964C>A · rs555646012 · VCV384435

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7474 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.54%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7474	likely pathogenic
REVEL	0.229	benign-leaning
SaProt	LLR -10.63	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.27	acceptor loss, 3 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	33.0	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 0.54% South Asian · 491/90,920 alleles

Filtering AF 0.501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.485%

Overall 0.0373% 601/1,613,058 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.54%	185
Middle Eastern	0.0661%	1,514
Remaining individualsnot grpmax-eligible	0.04%	2,499
Admixed American	0.00669%	14,945
European (non-Finnish)	0.00644%	15,520
East Asian	0.00223%	44,842

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.Pro655Gln
Coding: c.1964C>A
MANE Select: NM_001286577
dbSNP: rs555646012
Type: single nucleotide variant
Location: chr11:74106492 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 655: the c2 1 domain

Full C2CD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD3 c.3911-2A>T Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Arg621Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Arg666Ter Pathogenic ★★ same type
C2CD3 p.Arg768Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Tyr173Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 c.2085+5G>A Uncertain significance ★★ same type
C2CD3 c.4951+6C>T Uncertain significance ★★ same type
C2CD3 c.5495+4A>G Uncertain significance ★★ same type

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-pro655gln (accessed [today's date]).

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