Is EAF2 p.Leu251Val (c.751C>G) pathogenic?

EAF2 p.Leu251Val (c.751C>G) is classified Uncertain significance in EAF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-24). AlphaMissense: ambiguous (0.4935); Very rare (popmax 0.00443%, sas).

How common is EAF2 p.Leu251Val (c.751C>G) in the general population?

EAF2 p.Leu251Val (c.751C>G) is very rare (popmax 0.00443%, sas) (gnomAD).

What do computational predictors say about EAF2 p.Leu251Val (c.751C>G)?

AlphaMissense predicts ambiguous (score 0.4935) — an in-silico prediction, not a clinical call.

EAF2 p.Leu251Val

c.751C>G · VCV3274327

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4935 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00443%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4935	ambiguous
REVEL	0.161	moderately benign-leaning
SaProt	LLR -7.89	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.49	acceptor loss, 14 bp away · masked 0 · deltas
Pangolin	Δ0.33	gain · loss 0.28 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP 4	GERP 0.28, phastCons 1
Overall
CADD	21.2	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 0.00443% South Asian · 3/67,720 alleles

Filtering AF 0.00118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000626%

Overall 0.000225% 3/1,336,236 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: EAF2
Protein: p.Leu251Val
Coding: c.751C>G
MANE Select: NM_019100 · reported on NM_018456
Type: single nucleotide variant
Location: chr3:121886356 (GRCh38)
Structure: AlphaFold pLDDT 75.46 · 18 PDB
Residue 251: an α-helix

Full EAF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DMAP1 p.Arg224Ter Uncertain significance ★★ same type
DMAP1 p.Arg283His Uncertain significance ★★ ⚠ same type
DMAP1 p.Tyr196Ser Uncertain significance ★★ ⚠ same type
DMAP1 p.Arg226Trp Likely pathogenic ★ same type
DMAP1 c.1344+3A>G Uncertain significance ★ same type
DMAP1 c.394-1G>C Uncertain significance ★ same type
DMAP1 p.Ala207Thr Uncertain significance ★ ⚠ same type
DMAP1 p.Ala2Thr 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/eaf2-p-leu251val (accessed [today's date]).

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