Is CD1D p.Val99Glu (c.296T>A) pathogenic?

CD1D p.Val99Glu (c.296T>A) is classified Uncertain significance in CD1D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-13). AlphaMissense: likely pathogenic (0.631); Very rare (popmax 0.00267%, afr).

How common is CD1D p.Val99Glu (c.296T>A) in the general population?

CD1D p.Val99Glu (c.296T>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CD1D p.Val99Glu (c.296T>A)?

AlphaMissense predicts likely pathogenic (score 0.631) — an in-silico prediction, not a clinical call.

CD1D p.Val99Glu

c.296T>A · VCV3998055

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.631 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.631	likely pathogenic · top 7% in CD1D
REVEL	0.263	benign-leaning
SaProt	LLR -14.55	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 0.69, phastCons 0.88
Regional constraint	o/e 1.05	unconstrained · MANE · 3,045 bp · p 0.31 · regional, not allelic
Overall
CADD	22.2	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 0.00267% African / African-American · 2/74,914 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,612,238 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.Val99Glu
Coding: c.296T>A
MANE Select: NM_001371762
Type: single nucleotide variant
Location: chr1:158181689 (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.Val99Met 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-val99glu (accessed [today's date]).

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