Is ECE2 p.Leu591Val (c.1771C>G) pathogenic?

ECE2 p.Leu591Val (c.1771C>G) is classified Uncertain significance in ECE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-27). AlphaMissense: likely benign (0.2198); Ultra-rare (popmax 0.0538%, sas).

How common is ECE2 p.Leu591Val (c.1771C>G) in the general population?

ECE2 p.Leu591Val (c.1771C>G) is ultra-rare (popmax 0.0538%, sas) (gnomAD).

What do computational predictors say about ECE2 p.Leu591Val (c.1771C>G)?

AlphaMissense predicts likely benign (score 0.2198) — an in-silico prediction, not a clinical call.

ECE2 p.Leu591Val

c.1771C>G · rs775384008 · VCV2313074

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2198 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0538%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2198	likely benign
REVEL	0.459	indeterminate
SaProt	LLR -8.47	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.014 · regional, not allelic
Overall
CADD	21.6	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L637V vs ClinVar L591V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0538% South Asian · 49/91,090 alleles

Filtering AF 0.0417% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0374%

Overall 0.00304% 49/1,614,038 alleles · ultra-rare

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: ECE2
Protein: p.Leu591Val
Coding: c.1771C>G
MANE Select: NM_001100121
dbSNP: rs775384008
Type: single nucleotide variant
Location: chr3:184290797 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 591: a disulfide bond; the peptidase m13 domain

Full ECE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ECE2 p.Arg453Gln Benign ★★ same type
ECE2 p.Ser400= Benign ★★ same type
ECE2 p.Val248= Benign ★★ same type
EEF1AKMT4-ECE2 p.Val127Ala Benign ★★ ⚠ same type
ECE2 p.Ala338Val Uncertain significance ★ ⚠ same type
ECE2 p.Ala437Thr Uncertain significance ★ ⚠ same type
ECE2 p.Ala575Thr Uncertain significance ★ ⚠ same type
ECE2 p.Ala638Gly 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/ece2-p-leu591val (accessed [today's date]).

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