Is ENTHD1 p.Ile548Thr (c.1643T>C) pathogenic?

ENTHD1 p.Ile548Thr (c.1643T>C) is classified Uncertain significance in ENTHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.1112); Rare (popmax 0.61%, afr).

How common is ENTHD1 p.Ile548Thr (c.1643T>C) in the general population?

ENTHD1 p.Ile548Thr (c.1643T>C) is rare (popmax 0.61%, afr) (gnomAD).

What do computational predictors say about ENTHD1 p.Ile548Thr (c.1643T>C)?

AlphaMissense predicts likely benign (score 0.1112) — an in-silico prediction, not a clinical call.

ENTHD1 p.Ile548Thr

c.1643T>C · VCV4249268

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1112 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.61%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1112	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -6.11	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 5.4	GERP 0.56, phastCons 0.98
Regional constraint	o/e 0.88	unconstrained · MANE · 144 kb · p 0.0022 · regional, not allelic
Overall
CADD	10.65	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 0.61% African / African-American · 458/75,030 alleles

Filtering AF 0.564% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.546%

Overall 0.0327% 528/1,614,116 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.61%	164
Remaining individualsnot grpmax-eligible	0.0496%	2,016
Admixed American	0.0367%	2,728
Middle Eastern	0.0165%	6,062
South Asian	0.00329%	30,359
European (non-Finnish)	0.0011%	90,768

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.Ile548Thr
Coding: c.1643T>C
MANE Select: NM_152512
Type: single nucleotide variant
Location: chr22:39743860 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.58

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-ile548thr (accessed [today's date]).

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