Is C2CD3 p.Ile126Val (c.376A>G) pathogenic?

C2CD3 p.Ile126Val (c.376A>G) is classified Likely benign in C2CD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-10). AlphaMissense: likely benign (0.055); Ultra-rare (popmax 0.0331%, mid).

How common is C2CD3 p.Ile126Val (c.376A>G) in the general population?

C2CD3 p.Ile126Val (c.376A>G) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

What do computational predictors say about C2CD3 p.Ile126Val (c.376A>G)?

AlphaMissense predicts likely benign (score 0.055) — an in-silico prediction, not a clinical call.

C2CD3 p.Ile126Val

c.376A>G · VCV4913061

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.055 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.055	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -5.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.32	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -4.3	GERP -3.8
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	2.815	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 0.0331% Middle Eastern · 2/6,036 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00947%

Overall 0.00915% 146/1,595,318 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0331%	3,018
European (non-Finnish)	0.0117%	8,545
Remaining individualsnot grpmax-eligible	0.00486%	20,583
African / African-American	0.00406%	24,612
Admixed American	0.00174%	57,462

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.Ile126Val
Coding: c.376A>G
MANE Select: NM_001286577
Type: single nucleotide variant
Location: chr11:74161506 (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

Similar variants

C2CD3 p.Ile126Met Uncertain significance ★★ ⚠ same residue
C2CD3 p.Ile126Thr Uncertain significance ★ ⚠ same residue
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

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-ile126val (accessed [today's date]).

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