Is C2CD4D p.Leu329Val (c.985C>G) pathogenic?

C2CD4D p.Leu329Val (c.985C>G) is classified Uncertain significance in C2CD4D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely benign (0.1979); Ultra-rare (popmax 0.0214%, sas).

How common is C2CD4D p.Leu329Val (c.985C>G) in the general population?

C2CD4D p.Leu329Val (c.985C>G) is ultra-rare (popmax 0.0214%, sas) (gnomAD).

What do computational predictors say about C2CD4D p.Leu329Val (c.985C>G)?

AlphaMissense predicts likely benign (score 0.1979) — an in-silico prediction, not a clinical call.

C2CD4D p.Leu329Val

c.985C>G · VCV4217312

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1979 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0214%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1979	likely benign
REVEL	0.266	benign-leaning
SaProt	LLR -8.25	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 8.2	GERP 1.2, phastCons 1
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0214% South Asian · 18/84,010 alleles

Filtering AF 0.0138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.0035% 49/1,398,852 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0214%	4,667
Ashkenazi Jewishnot grpmax-eligible	0.0209%	4,774
Remaining individualsnot grpmax-eligible	0.00832%	12,019
European (non-Finnish)	0.00174%	57,338

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: C2CD4D
Protein: p.Leu329Val
Coding: c.985C>G
MANE Select: NM_001394591
Type: single nucleotide variant
Location: chr1:151838005 (GRCh38)
Gene constraint: LOEUF 1.931 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 66.41
Residue 329: the c2 domain

Full C2CD4D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD4D p.Ala120Val Uncertain significance ★ ⚠ same type
C2CD4D p.Ala301Gly Uncertain significance ★ ⚠ same type
C2CD4D p.Ala31Ser Uncertain significance ★ ⚠ same type
C2CD4D p.Ala38Pro Uncertain significance ★ ⚠ same type
C2CD4D p.Ala63Glu Uncertain significance ★ ⚠ same type
C2CD4D p.Ala78Thr Uncertain significance ★ ⚠ same type
C2CD4D p.Arg102Trp Uncertain significance ★ ⚠ same type
C2CD4D p.Arg185His 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/c2cd4d-p-leu329val (accessed [today's date]).

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