Is EDEM2 p.Leu555Phe (c.1663C>T) pathogenic?

EDEM2 p.Leu555Phe (c.1663C>T) is classified Uncertain significance in EDEM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). AlphaMissense: likely benign (0.0674); Ultra-rare (popmax 0.0133%, amr).

How common is EDEM2 p.Leu555Phe (c.1663C>T) in the general population?

EDEM2 p.Leu555Phe (c.1663C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about EDEM2 p.Leu555Phe (c.1663C>T)?

AlphaMissense predicts likely benign (score 0.0674) — an in-silico prediction, not a clinical call.

EDEM2 p.Leu555Phe

c.1663C>T · VCV3506658

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0674 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0674	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -7.25	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 6.6	GERP 0.84, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 32 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	21.3	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 0.0133% Admixed American · 8/60,026 alleles

Filtering AF 0.00876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0082%

Overall 0.00824% 133/1,614,058 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,503
European (non-Finnish)	0.0103%	9,752
Remaining individualsnot grpmax-eligible	0.0064%	15,622

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.Leu555Phe
Coding: c.1663C>T
MANE Select: NM_018217
Type: single nucleotide variant
Location: chr20:35115507 (GRCh38)
Gene constraint: LOEUF 0.749 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.61
Residue 555: the 'disordered' region

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-leu555phe (accessed [today's date]).

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