Is EME1 p.Ile252Phe (c.754A>T) pathogenic?

EME1 p.Ile252Phe (c.754A>T) is classified Uncertain significance in EME1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-30). AlphaMissense: likely benign (0.3204); Very rare (popmax 8.51e-05%, nfe).

How common is EME1 p.Ile252Phe (c.754A>T) in the general population?

EME1 p.Ile252Phe (c.754A>T) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about EME1 p.Ile252Phe (c.754A>T)?

AlphaMissense predicts likely benign (score 0.3204) — an in-silico prediction, not a clinical call.

EME1 p.Ile252Phe

c.754A>T · VCV4017745

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3204 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3204	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -7.93	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 0.41	GERP -0.87, phastCons 0.061
Regional constraint	o/e 0.93	unconstrained · MANE · 5,727 bp · p 0.068 · regional, not allelic
Overall
CADD	18.01	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 8.51e-05% European (non-Finnish) · 1/1,175,572 alleles

Overall 6.22e-05% 1/1,607,244 alleles · very rare exomes 1/1,454,902 · genomes 0/152,342 · joint denominator

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: EME1
Protein: p.Ile252Phe
Coding: c.754A>T
MANE Select: NM_152463
Type: single nucleotide variant
Location: chr17:50375962 (GRCh38)
Gene constraint: LOEUF 1.248 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.81 · 14 PDB
Residue 252: the 'nuclease-like domain; forms the post-nick dna binding interface and is involved in dna recognition and bending' region

Full EME1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EME1 p.Ile252Val Likely benign ★ same residue
EME1 p.Ile282Thr Uncertain significance ★★ same type
EME1 p.Lys5Asn Benign ★★ same type
EME1 c.1113-24C>G Uncertain significance ★ same type
EME1 c.1113-33G>T Uncertain significance ★ same type
EME1 c.1113-34A>G Uncertain significance ★ same type
EME1 c.1113-8T>C Uncertain significance ★ same type
EME1 p.Ala235Val 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/eme1-p-ile252phe (accessed [today's date]).

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