Is C2CD3 p.Leu2180Val (c.6538C>G) pathogenic?

C2CD3 p.Leu2180Val (c.6538C>G) is classified Likely benign in C2CD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-02). AlphaMissense: likely benign (0.0666); Ultra-rare (popmax 0.0356%, afr).

How common is C2CD3 p.Leu2180Val (c.6538C>G) in the general population?

C2CD3 p.Leu2180Val (c.6538C>G) is ultra-rare (popmax 0.0356%, afr) (gnomAD).

What do computational predictors say about C2CD3 p.Leu2180Val (c.6538C>G)?

AlphaMissense predicts likely benign (score 0.0666) — an in-silico prediction, not a clinical call.

C2CD3 p.Leu2180Val

c.6538C>G · rs988699534 · VCV2421808

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0666 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0356%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0666	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -6.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.30	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 1.4	GERP 0.84, phastCons 0.001
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	0.919	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 0.0356% African / African-American · 26/73,018 alleles

Filtering AF 0.0249% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00169% 26/1,536,070 alleles · ultra-rare

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.Leu2180Val
Coding: c.6538C>G
MANE Select: NM_001286577
dbSNP: rs988699534
Type: single nucleotide variant
Location: chr11:74033622 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 2180: the 'disordered' region

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-leu2180val (accessed [today's date]).

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