Is ENTHD1 p.Leu43Phe (c.129G>T) pathogenic?

ENTHD1 p.Leu43Phe (c.129G>T) is classified Uncertain significance in ENTHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-16). AlphaMissense: ambiguous (0.4594); Very rare (popmax 0.000169%, nfe).

How common is ENTHD1 p.Leu43Phe (c.129G>T) in the general population?

ENTHD1 p.Leu43Phe (c.129G>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ENTHD1 p.Leu43Phe (c.129G>T)?

AlphaMissense predicts ambiguous (score 0.4594) — an in-silico prediction, not a clinical call.

ENTHD1 p.Leu43Phe

c.129G>T · VCV3508669

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4594 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4594	ambiguous
REVEL	0.318	indeterminate
SaProt	LLR -9.76	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 144 kb · p 0.0022 · regional, not allelic
Overall
CADD	22.5	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 0.000169% European (non-Finnish) · 2/1,180,022 alleles

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

Overall 0.000137% 2/1,461,880 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: ENTHD1
Protein: p.Leu43Phe
Coding: c.129G>T
MANE Select: NM_152512
Type: single nucleotide variant
Location: chr22:39887620 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.58
Residue 43: the enth domain

Full ENTHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENTHD1 p.Ala112Ser Uncertain significance ★ ⚠ same type
ENTHD1 p.Ala144Gly Uncertain significance ★ ⚠ same type
ENTHD1 p.Ala170Val Uncertain significance ★ ⚠ same type
ENTHD1 p.Ala385Gly Uncertain significance ★ ⚠ same type
ENTHD1 p.Arg121Trp Uncertain significance ★ ⚠ same type
ENTHD1 p.Arg141Met Uncertain significance ★ ⚠ same type
ENTHD1 p.Arg146Gln Uncertain significance ★ ⚠ same type
ENTHD1 p.Arg160Thr 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/enthd1-p-leu43phe (accessed [today's date]).

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