Is EDEM3 p.Val142Ile (c.424G>A) pathogenic?

EDEM3 p.Val142Ile (c.424G>A) is classified Uncertain significance in EDEM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-16). AlphaMissense: likely benign (0.2159); Very rare (popmax 0.00714%, eas); Associated with Inborn genetic diseases.

What condition is associated with EDEM3 p.Val142Ile (c.424G>A)?

EDEM3 p.Val142Ile (c.424G>A) is associated with Inborn genetic diseases (ClinVar).

How common is EDEM3 p.Val142Ile (c.424G>A) in the general population?

EDEM3 p.Val142Ile (c.424G>A) is very rare (popmax 0.00714%, eas) (gnomAD).

What do computational predictors say about EDEM3 p.Val142Ile (c.424G>A)?

AlphaMissense predicts likely benign (score 0.2159) — an in-silico prediction, not a clinical call.

EDEM3 p.Val142Ile

c.424G>A · VCV4016207

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2159 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00714%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2159	likely benign
REVEL	0.343	indeterminate
SaProt	LLR -9.15	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 5.1, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 20 kb · p 0.23 · regional, not allelic
Overall
CADD	28.3	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 0.00714% East Asian · 3/42,018 alleles

Filtering AF 0.00189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.00136% 21/1,545,160 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00714%	14,006
African / African-American	0.00552%	18,128
Admixed American	0.00372%	26,874
Remaining individualsnot grpmax-eligible	0.00169%	59,252
European (non-Finnish)	0.000963%	103,874

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: EDEM3
Protein: p.Val142Ile
Coding: c.424G>A
MANE Select: NM_025191
Type: single nucleotide variant
Location: chr1:184734565 (GRCh38)
Gene constraint: LOEUF 0.671 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.50

Full EDEM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EDEM3 p.Arg579Lys Uncertain significance ★★ ⚠ same condition
EDEM3 p.Asn691Ser Uncertain significance ★★ ⚠ same condition
EDEM3 p.His454Gln Uncertain significance ★★ ⚠ same condition
EDEM3 p.Pro574Ser Uncertain significance ★★ ⚠ same condition
EDEM3 p.Ala17Gly Conflicting classifications of pathogenicity ★ ⚠ same condition
EDEM3 p.Ala245Thr Uncertain significance ★ ⚠ same condition
EDEM3 p.Ala41Val Uncertain significance ★ ⚠ same condition
EDEM3 p.Ala437Ser Uncertain significance ★ ⚠ same condition

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/edem3-p-val142ile (accessed [today's date]).

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