Is EDEM2 p.Val247Ala (c.740T>C) pathogenic?

EDEM2 p.Val247Ala (c.740T>C) is classified Uncertain significance in EDEM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: ambiguous (0.3618); Very rare (popmax 0.000678%, nfe).

How common is EDEM2 p.Val247Ala (c.740T>C) in the general population?

EDEM2 p.Val247Ala (c.740T>C) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about EDEM2 p.Val247Ala (c.740T>C)?

AlphaMissense predicts ambiguous (score 0.3618) — an in-silico prediction, not a clinical call.

EDEM2 p.Val247Ala

c.740T>C · VCV4246585

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3618 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3618	ambiguous
REVEL	0.425	indeterminate
SaProt	LLR -9.23	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 32 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	27.5	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 0.000678% European (non-Finnish) · 8/1,180,014 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,614,002 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: EDEM2
Protein: p.Val247Ala
Coding: c.740T>C
MANE Select: NM_018217
Type: single nucleotide variant
Location: chr20:35131746 (GRCh38)
Gene constraint: LOEUF 0.749 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.61

Full EDEM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EDEM2 p.Ala251Thr Uncertain significance ★ ⚠ same type
EDEM2 p.Ala484Thr Uncertain significance ★ ⚠ same type
EDEM2 p.Ala529Glu Uncertain significance ★ ⚠ same type
EDEM2 p.Ala81Thr Uncertain significance ★ ⚠ same type
EDEM2 p.Arg219Thr Uncertain significance ★ ⚠ same type
EDEM2 p.Arg224Cys Uncertain significance ★ ⚠ same type
EDEM2 p.Arg224His Uncertain significance ★ ⚠ same type
EDEM2 p.Arg229Gln 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/edem2-p-val247ala (accessed [today's date]).

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