Is EDEM2 p.Val257Met (c.769G>A) pathogenic?

EDEM2 p.Val257Met (c.769G>A) is classified Uncertain significance in EDEM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). AlphaMissense: likely pathogenic (0.5829); Ultra-rare (popmax 0.0468%, eas).

How common is EDEM2 p.Val257Met (c.769G>A) in the general population?

EDEM2 p.Val257Met (c.769G>A) is ultra-rare (popmax 0.0468%, eas) (gnomAD).

What do computational predictors say about EDEM2 p.Val257Met (c.769G>A)?

AlphaMissense predicts likely pathogenic (score 0.5829) — an in-silico prediction, not a clinical call.

EDEM2 p.Val257Met

c.769G>A · VCV4016204

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5829 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0468%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5829	likely pathogenic
REVEL	0.263	benign-leaning
SaProt	LLR -12.64	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 32 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	31.0	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 0.0468% East Asian · 21/44,886 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0263%

Overall 0.00198% 32/1,614,202 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0468%	2,137
Admixed American	0.00333%	30,013
South Asian	0.0011%	91,086
European (non-Finnish)	0.000678%	147,505

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.Val257Met
Coding: c.769G>A
MANE Select: NM_018217
Type: single nucleotide variant
Location: chr20:35131717 (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-val257met (accessed [today's date]).

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