Is EDEM3 p.Pro12Leu (c.35C>T) pathogenic?

EDEM3 p.Pro12Leu (c.35C>T) is classified Uncertain significance in EDEM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: likely benign (0.0942); Very rare (popmax 0.000595%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EDEM3 p.Pro12Leu (c.35C>T)?

EDEM3 p.Pro12Leu (c.35C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EDEM3 p.Pro12Leu (c.35C>T) in the general population?

EDEM3 p.Pro12Leu (c.35C>T) is very rare (popmax 0.000595%, nfe) (gnomAD).

What do computational predictors say about EDEM3 p.Pro12Leu (c.35C>T)?

AlphaMissense predicts likely benign (score 0.0942) — an in-silico prediction, not a clinical call.

EDEM3 p.Pro12Leu

c.35C>T · rs1262253084 · VCV2235304

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000595%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0942	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -7.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP 0.073, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 20 kb · p 0.23 · regional, not allelic
Overall
CADD	16.91	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 0.000595% European (non-Finnish) · 7/1,176,354 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000436% 7/1,605,352 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: EDEM3
Protein: p.Pro12Leu
Coding: c.35C>T
MANE Select: NM_025191
dbSNP: rs1262253084
Type: single nucleotide variant
Location: chr1:184754612 (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-pro12leu (accessed [today's date]).

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