Is C2CD3 p.Ala2041Val (c.6122C>T) pathogenic?

C2CD3 p.Ala2041Val (c.6122C>T) is classified Benign in C2CD3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0855); Low-frequency (popmax 2.05%, mid).

How common is C2CD3 p.Ala2041Val (c.6122C>T) in the general population?

C2CD3 p.Ala2041Val (c.6122C>T) is low-frequency (popmax 2.05%, mid) (gnomAD).

What do computational predictors say about C2CD3 p.Ala2041Val (c.6122C>T)?

AlphaMissense predicts likely benign (score 0.0855) — an in-silico prediction, not a clinical call.

C2CD3 p.Ala2041Val

c.6122C>T · rs145765035 · VCV1532653

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0855 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.05%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0855	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -6.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.3	GERP -0.22
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	3.651	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 2.05% Middle Eastern · 123/5,992 alleles

Filtering AF 1.76% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.65%

Overall 0.993% 15,257/1,536,458 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	2.05%	49
South Asian	1.44%	69
Ashkenazi Jewishnot grpmax-eligible	1.38%	72
European (non-Finnish)	1.06%	94
Remaining individualsnot grpmax-eligible	1.05%	95
Admixed American	0.933%	107
Finnishnot grpmax-eligible	0.21%	475
African / African-American	0.164%	610
East Asian	0.00977%	10,231

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.Ala2041Val
Coding: c.6122C>T
MANE Select: NM_001286577
dbSNP: rs145765035
Type: single nucleotide variant
Location: chr11:74034038 (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 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-ala2041val (accessed [today's date]).

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