Is ENTHD1 p.Ser594Pro (c.1780T>C) pathogenic?

ENTHD1 p.Ser594Pro (c.1780T>C) is classified Uncertain significance in ENTHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-29). AlphaMissense: likely benign (0.0895); Very rare (popmax 0.00223%, eas).

How common is ENTHD1 p.Ser594Pro (c.1780T>C) in the general population?

ENTHD1 p.Ser594Pro (c.1780T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ENTHD1 p.Ser594Pro (c.1780T>C)?

AlphaMissense predicts likely benign (score 0.0895) — an in-silico prediction, not a clinical call.

ENTHD1 p.Ser594Pro

c.1780T>C · VCV3275523

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0895 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0895	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -7.62	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 -0.17	GERP -0.77
Regional constraint	o/e 0.88	unconstrained · MANE · 144 kb · p 0.0022 · regional, not allelic
Overall
CADD	12.69	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 0.00223% East Asian · 1/44,886 alleles

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

Overall 0.000186% 3/1,613,826 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,886
European (non-Finnish)	0.00017%	589,911

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.Ser594Pro
Coding: c.1780T>C
MANE Select: NM_152512
Type: single nucleotide variant
Location: chr22:39743723 (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-ser594pro (accessed [today's date]).

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