Is EEPD1 p.Leu489Pro (c.1466T>C) pathogenic?

EEPD1 p.Leu489Pro (c.1466T>C) is classified Uncertain significance in EEPD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-26). AlphaMissense: ambiguous (0.5249); Ultra-rare (popmax 0.0223%, eas).

How common is EEPD1 p.Leu489Pro (c.1466T>C) in the general population?

EEPD1 p.Leu489Pro (c.1466T>C) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about EEPD1 p.Leu489Pro (c.1466T>C)?

AlphaMissense predicts ambiguous (score 0.5249) — an in-silico prediction, not a clinical call.

EEPD1 p.Leu489Pro

c.1466T>C · VCV3274583

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5249 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5249	ambiguous
REVEL	0.964	strongly pathogenic-leaning
SaProt	LLR -8.21	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 145 kb · p 0.0078 · regional, not allelic
Overall
CADD	25.5	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 0.0223% East Asian · 10/44,882 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00916%

Overall 0.000743% 12/1,614,218 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,488
Remaining individualsnot grpmax-eligible	0.0032%	31,256

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: EEPD1
Protein: p.Leu489Pro
Coding: c.1466T>C
MANE Select: NM_030636
Type: single nucleotide variant
Location: chr7:36297143 (GRCh38)
Gene constraint: LOEUF 0.561 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 74.72 · 3 PDB

Full EEPD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EEPD1 p.Ala107Gly Uncertain significance ★ ⚠ same type
EEPD1 p.Ala120Gly Uncertain significance ★ ⚠ same type
EEPD1 p.Ala130Val Uncertain significance ★ ⚠ same type
EEPD1 p.Ala186Pro Uncertain significance ★ ⚠ same type
EEPD1 p.Ala186Thr Uncertain significance ★ ⚠ same type
EEPD1 p.Ala215Thr Uncertain significance ★ ⚠ same type
EEPD1 p.Ala349Val Uncertain significance ★ ⚠ same type
EEPD1 p.Ala352Glu 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/eepd1-p-leu489pro (accessed [today's date]).

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