Is CD1E p.Val259Ile (c.775G>A) pathogenic?

CD1E p.Val259Ile (c.775G>A) is classified Likely benign in CD1E (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-22). AlphaMissense: likely benign (0.0674); Very rare (popmax 0.005%, amr).

How common is CD1E p.Val259Ile (c.775G>A) in the general population?

CD1E p.Val259Ile (c.775G>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CD1E p.Val259Ile (c.775G>A)?

AlphaMissense predicts likely benign (score 0.0674) — an in-silico prediction, not a clinical call.

CD1E p.Val259Ile

c.775G>A · rs764692539 · VCV2256369

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0674 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0674	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -4.70	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 -15	GERP -3.7
Regional constraint	o/e 1.04	unconstrained · MANE · 2,904 bp · p 0.34 · regional, not allelic
Overall
CADD	0.001	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 0.005% Admixed American · 3/59,992 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00353% 57/1,613,992 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0112%	8,927
Admixed Americangrpmax	0.005%	19,997
East Asian	0.00446%	22,433
European (non-Finnish)	0.00373%	26,819
African / African-American	0.00134%	74,886

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val259Ile
Coding: c.775G>A
MANE Select: NM_030893
dbSNP: rs764692539
Type: single nucleotide variant
Location: chr1:158355976 (GRCh38)
Gene constraint: LOEUF 1.517 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.66 · 1 PDB
Residue 259: the ig-like domain; a disulfide bond

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-val259ile (accessed [today's date]).

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