Is CD1D p.Val99Met (c.295G>A) pathogenic?

CD1D p.Val99Met (c.295G>A) is classified Uncertain significance in CD1D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely benign (0.1561); Very rare (popmax 0.000169%, nfe).

How common is CD1D p.Val99Met (c.295G>A) in the general population?

CD1D p.Val99Met (c.295G>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CD1D p.Val99Met (c.295G>A)?

AlphaMissense predicts likely benign (score 0.1561) — an in-silico prediction, not a clinical call.

CD1D p.Val99Met

c.295G>A · VCV3829428

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1561 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1561	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -8.09	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 -9.9	GERP -3.8
Regional constraint	o/e 1.05	unconstrained · MANE · 3,045 bp · p 0.31 · regional, not allelic
Overall
CADD	0.155	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 0.000169% European (non-Finnish) · 2/1,180,030 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,612,304 alleles · very 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: CD1D
Protein: p.Val99Met
Coding: c.295G>A
MANE Select: NM_001371762
Type: single nucleotide variant
Location: chr1:158181688 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.20 · 23 PDB
Residue 99: an α-helix

Full CD1D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD1D p.Val99Glu Uncertain significance ★ ⚠ same residue
CD1D p.Thr64Ser Benign ★★ same type
CD1D p.Ala118Ser Uncertain significance ★ ⚠ same type
CD1D p.Ala11Glu Uncertain significance ★ ⚠ same type
CD1D p.Ala306Ser Uncertain significance ★ ⚠ same type
CD1D p.Ala311Val Uncertain significance ★ ⚠ same type
CD1D p.Arg211His Uncertain significance ★ ⚠ same type
CD1D p.Arg24Lys 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/cd1d-p-val99met (accessed [today's date]).

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