Is ECE1 p.Pro449Ala (c.1345C>G) pathogenic?

ECE1 p.Pro449Ala (c.1345C>G) is classified Uncertain significance in ECE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-03). AlphaMissense: likely benign (0.087); Very rare (popmax 0.00695%, nfe).

How common is ECE1 p.Pro449Ala (c.1345C>G) in the general population?

ECE1 p.Pro449Ala (c.1345C>G) is very rare (popmax 0.00695%, nfe) (gnomAD).

What do computational predictors say about ECE1 p.Pro449Ala (c.1345C>G)?

AlphaMissense predicts likely benign (score 0.087) — an in-silico prediction, not a clinical call.

ECE1 p.Pro449Ala

c.1345C>G · rs146655154 · VCV2208887

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.087 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00695%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.087	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	LLR -4.57	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 8.1	GERP 0.88, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 27 kb · p 1.3e-06 · regional, not allelic
Overall
CADD	17.78	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 0.00695% European (non-Finnish) · 82/1,180,050 alleles

Filtering AF 0.00571% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.00545% 88/1,614,106 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00695%	14,391
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Admixed American	0.00333%	30,001
African / African-American	0.00133%	74,936

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.Pro449Ala
Coding: c.1345C>G
MANE Select: NM_001397
dbSNP: rs146655154
Type: single nucleotide variant
Location: chr1:21238178 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 91.16 · 1 PDB
Residue 449: a disulfide bond; the peptidase m13 domain; an α-helix

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-pro449ala (accessed [today's date]).

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