Is CD1E p.Leu349Phe (c.1045C>T) pathogenic?

CD1E p.Leu349Phe (c.1045C>T) is classified Uncertain significance in CD1E (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). AlphaMissense: likely benign (0.0765); Ultra-rare (popmax 0.0367%, amr).

How common is CD1E p.Leu349Phe (c.1045C>T) in the general population?

CD1E p.Leu349Phe (c.1045C>T) is ultra-rare (popmax 0.0367%, amr) (gnomAD).

What do computational predictors say about CD1E p.Leu349Phe (c.1045C>T)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

CD1E p.Leu349Phe

c.1045C>T · rs746581112 · VCV3140403

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	LLR -7.36	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 -2.9	GERP -3.2
Regional constraint	o/e 1.04	unconstrained · MANE · 2,904 bp · p 0.34 · regional, not allelic
Overall
CADD	0.361	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 0.0367% Admixed American · 22/59,956 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.00143% 23/1,613,652 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0367%	2,725
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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: CD1E
Protein: p.Leu349Phe
Coding: c.1045C>T
MANE Select: NM_030893
dbSNP: rs746581112
Type: single nucleotide variant
Location: chr1:158356774 (GRCh38)
Gene constraint: LOEUF 1.517 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.66 · 1 PDB

Full CD1E gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD1E p.Asp264= Benign ★★ same type
CD1E p.His102Arg Benign ★★ same type
CD1E p.Ala110Val Uncertain significance ★ ⚠ same type
CD1E p.Ala127Thr Uncertain significance ★ ⚠ same type
CD1E p.Ala195Val Uncertain significance ★ ⚠ same type
CD1E p.Arg164Trp Uncertain significance ★ ⚠ same type
CD1E p.Arg192Gln Uncertain significance ★ ⚠ same type
CD1E p.Arg207Trp 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/cd1e-p-leu349phe (accessed [today's date]).

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