Is C2CD3 p.Pro125Ala (c.373C>G) pathogenic?

C2CD3 p.Pro125Ala (c.373C>G) is classified Uncertain significance in C2CD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-16). AlphaMissense: likely benign (0.1734); Ultra-rare (popmax 0.0166%, mid); Associated with Inborn genetic diseases.

What condition is associated with C2CD3 p.Pro125Ala (c.373C>G)?

C2CD3 p.Pro125Ala (c.373C>G) is associated with Inborn genetic diseases (ClinVar).

How common is C2CD3 p.Pro125Ala (c.373C>G) in the general population?

C2CD3 p.Pro125Ala (c.373C>G) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about C2CD3 p.Pro125Ala (c.373C>G)?

AlphaMissense predicts likely benign (score 0.1734) — an in-silico prediction, not a clinical call.

C2CD3 p.Pro125Ala

c.373C>G · VCV3262453

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1734 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1734	likely benign
REVEL	0.658	pathogenic-leaning
SaProt	LLR -7.67	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	25.0	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 0.0166% Middle Eastern · 1/6,008 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000278% 4/1,441,380 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,008
European (non-Finnish)	0.000256%	389,897

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.Pro125Ala
Coding: c.373C>G
MANE Select: NM_001286577
Type: single nucleotide variant
Location: chr11:74161509 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C2CD3 c.2085+5G>A Uncertain significance ★★ same condition
C2CD3 c.4951+6C>T Uncertain significance ★★ same condition
C2CD3 p.Ala1382Pro Uncertain significance ★★ ⚠ same condition
C2CD3 p.Ala1777Thr Uncertain significance ★★ ⚠ same condition
C2CD3 p.Ala95Thr Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1122Ile Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1145His Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1183His 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-pro125ala (accessed [today's date]).

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