Is CD1D p.Leu112Ser (c.335T>C) pathogenic?

CD1D p.Leu112Ser (c.335T>C) is classified Uncertain significance in CD1D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: ambiguous (0.4195); Very rare (popmax 0.00213%, nfe).

How common is CD1D p.Leu112Ser (c.335T>C) in the general population?

CD1D p.Leu112Ser (c.335T>C) is very rare (popmax 0.00213%, nfe) (gnomAD).

What do computational predictors say about CD1D p.Leu112Ser (c.335T>C)?

AlphaMissense predicts ambiguous (score 0.4195) — an in-silico prediction, not a clinical call.

CD1D p.Leu112Ser

c.335T>C · rs199803276 · VCV3140394

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4195 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00213%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4195	ambiguous
REVEL	0.169	moderately benign-leaning
SaProt	LLR -14.51	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP 0.71, phastCons 0.017
Regional constraint	o/e 1.05	unconstrained · MANE · 3,045 bp · p 0.31 · regional, not allelic
Overall
CADD	20.4	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 0.00213% European (non-Finnish) · 25/1,175,588 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00162% 26/1,605,918 alleles · very rare exomes 25/1,453,582 · genomes 1/152,336 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00213%	47,023
African / African-American	0.00134%	74,682

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.Leu112Ser
Coding: c.335T>C
MANE Select: NM_001371762
dbSNP: rs199803276
Type: single nucleotide variant
Location: chr1:158182038 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.20 · 23 PDB
Residue 112: a β-strand

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

Similar variants

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
CD1D p.Arg280Gly 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-leu112ser (accessed [today's date]).

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