Is ECE1 p.Val605Met (c.1813G>A) pathogenic?

ECE1 p.Val605Met (c.1813G>A) is classified Uncertain significance in ECE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-22). AlphaMissense: ambiguous (0.3797); Very rare (popmax 0.00329%, sas).

How common is ECE1 p.Val605Met (c.1813G>A) in the general population?

ECE1 p.Val605Met (c.1813G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about ECE1 p.Val605Met (c.1813G>A)?

AlphaMissense predicts ambiguous (score 0.3797) — an in-silico prediction, not a clinical call.

ECE1 p.Val605Met

c.1813G>A · VCV3506422

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3797 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Computational evidence

Protein change
AlphaMissense	0.3797	ambiguous
REVEL	0.385	indeterminate
SaProt	LLR -5.32	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP -1.5, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 27 kb · p 1.3e-06 · regional, not allelic
Overall
CADD	21.1	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 0.00329% South Asian · 3/91,086 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000547% 8/1,461,796 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,362
African / African-American	0.00266%	37,525
Admixed American	0.00167%	60,026
European (non-Finnish)	0.000169%	589,988

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.Val605Met
Coding: c.1813G>A
MANE Select: NM_001397
Type: single nucleotide variant
Location: chr1:21227195 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 91.16 · 1 PDB
Residue 605: 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-val605met (accessed [today's date]).

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