Is ECE1 p.Pro138Leu (c.413C>T) pathogenic?

ECE1 p.Pro138Leu (c.413C>T) is classified Uncertain significance in ECE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-21). AlphaMissense: ambiguous (0.4988); Ultra-rare (popmax 0.0786%, afr).

How common is ECE1 p.Pro138Leu (c.413C>T) in the general population?

ECE1 p.Pro138Leu (c.413C>T) is ultra-rare (popmax 0.0786%, afr) (gnomAD).

What do computational predictors say about ECE1 p.Pro138Leu (c.413C>T)?

AlphaMissense predicts ambiguous (score 0.4988) — an in-silico prediction, not a clinical call.

ECE1 p.Pro138Leu

c.413C>T · VCV3506414

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4988 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0786%, afr)

Computational evidence

Protein change
AlphaMissense	0.4988	ambiguous
REVEL	0.618	indeterminate
SaProt	LLR -11.24	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 32 kb · p 0.19 · regional, not allelic
Overall
CADD	31.0	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 0.0786% African / African-American · 59/75,070 alleles

Filtering AF 0.0625% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0567%

Overall 0.00626% 101/1,614,290 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0786%	1,272
Middle Eastern	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.0112%	8,930
Admixed American	0.00999%	10,006
South Asian	0.00439%	22,773
European (non-Finnish)	0.00178%	56,193

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.Pro138Leu
Coding: c.413C>T
MANE Select: NM_001397
Type: single nucleotide variant
Location: chr1:21272779 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 91.16 · 1 PDB
Residue 138: a disulfide bond; 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-pro138leu (accessed [today's date]).

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