Is ECE1 p.Leu482Pro (c.1445T>C) pathogenic?

ECE1 p.Leu482Pro (c.1445T>C) is classified Uncertain significance in ECE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-23). AlphaMissense: likely pathogenic (0.9629); Ultra-rare (popmax 0.0362%, afr).

How common is ECE1 p.Leu482Pro (c.1445T>C) in the general population?

ECE1 p.Leu482Pro (c.1445T>C) is ultra-rare (popmax 0.0362%, afr) (gnomAD).

What do computational predictors say about ECE1 p.Leu482Pro (c.1445T>C)?

AlphaMissense predicts likely pathogenic (score 0.9629) — an in-silico prediction, not a clinical call.

ECE1 p.Leu482Pro

c.1445T>C · rs144737209 · VCV2602243

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9629 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0362%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9629	likely pathogenic
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -15.87	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 27 kb · p 1.3e-06 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0362% African / African-American · 27/74,630 alleles

Filtering AF 0.0255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.022%

Overall 0.00198% 32/1,613,186 alleles · ultra-rare exomes 11/1,461,862 · genomes 21/151,324 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0362%	2,764
Middle Eastern	0.0164%	6,082
Admixed American	0.00501%	19,955
Remaining individualsnot grpmax-eligible	0.0016%	62,464

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: ECE1
Protein: p.Leu482Pro
Coding: c.1445T>C
MANE Select: NM_001397
dbSNP: rs144737209
Type: single nucleotide variant
Location: chr1:21236789 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 91.16 · 1 PDB
Residue 482: the peptidase m13 domain

Full ECE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ECE1 p.Thr312Met Uncertain significance ★★ ⚠ same type
ECE1 c.1020+15G>A Benign ★★ same type
ECE1 c.1164-5C>T Benign ★★ same type
ECE1 c.1278+7C>T Benign ★★ same type
ECE1 c.1782-4C>A Benign ★★ same type
ECE1 c.828+8T>C Benign ★★ same type
ECE1 p.Asn397Ser Benign ★★ same type
ECE1 p.Asp547= Benign ★★ 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/ece1-p-leu482pro (accessed [today's date]).

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