Is EAF1 p.Leu249Arg (c.746T>G) pathogenic?

EAF1 p.Leu249Arg (c.746T>G) is classified Uncertain significance in EAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-10). AlphaMissense: ambiguous (0.4734); Absent from gnomAD v4.1.

How common is EAF1 p.Leu249Arg (c.746T>G) in the general population?

EAF1 p.Leu249Arg (c.746T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EAF1 p.Leu249Arg (c.746T>G)?

AlphaMissense predicts ambiguous (score 0.4734) — an in-silico prediction, not a clinical call.

EAF1 p.Leu249Arg

c.746T>G · VCV3843214

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4734 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.4734	ambiguous
REVEL	0.39	indeterminate
SaProt	LLR -9.35	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 11 kb · p 3.8e-05 · regional, not allelic
Overall
CADD	26.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EAF1
Protein: p.Leu249Arg
Coding: c.746T>G
MANE Select: NM_033083
Type: single nucleotide variant
Location: chr3:15436561 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.79 · 2 PDB
Residue 249: the 'disordered' region; the 'necessary for transactivation activity' region

Full EAF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EAF1 p.Asp206= Benign ★★ same type
EAF1 p.Thr133= Benign ★★ same type
EAF1 p.Ala147Ser Uncertain significance ★ ⚠ same type
EAF1 p.Arg122Gln Uncertain significance ★ ⚠ same type
EAF1 p.Arg233Met Uncertain significance ★ ⚠ same type
EAF1 p.Arg233Thr Uncertain significance ★ ⚠ same type
EAF1 p.Arg27Gln Uncertain significance ★ ⚠ same type
EAF1 p.Asn216Ser 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/eaf1-p-leu249arg (accessed [today's date]).

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