Is ECE1 p.Arg618Gln (c.1853G>A) pathogenic?

ECE1 p.Arg618Gln (c.1853G>A) is classified Uncertain significance in ECE1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-01-05). AlphaMissense: likely pathogenic (0.7081); Ultra-rare (popmax 0.012%, afr); Associated with ECE1-related disorder.

What condition is associated with ECE1 p.Arg618Gln (c.1853G>A)?

ECE1 p.Arg618Gln (c.1853G>A) is associated with ECE1-related disorder (ClinVar).

How common is ECE1 p.Arg618Gln (c.1853G>A) in the general population?

ECE1 p.Arg618Gln (c.1853G>A) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about ECE1 p.Arg618Gln (c.1853G>A)?

AlphaMissense predicts likely pathogenic (score 0.7081) — an in-silico prediction, not a clinical call.

ECE1 p.Arg618Gln

c.1853G>A · rs760171613 · VCV3029233

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7081 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ECE1-related disorder

Computational evidence

Protein change
AlphaMissense	0.7081	likely pathogenic
REVEL	0.886	moderately pathogenic-leaning
SaProt	LLR -10.06	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.70	acceptor gain · deltas
Pangolin	Δ0.22	gain · loss 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 27 kb · p 1.3e-06 · regional, not allelic
Overall
CADD	36.0	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 0.012% African / African-American · 9/74,918 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00124% 20/1,613,830 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,324
European (non-Finnish)	0.000932%	107,269

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.Arg618Gln
Coding: c.1853G>A
MANE Select: NM_001397
dbSNP: rs760171613
Type: single nucleotide variant
Location: chr1:21225437 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 91.16 · 1 PDB
Residue 618: a disulfide bond; the peptidase m13 domain; an α-helix

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

Disease context

ECE1-related disorder

Similar variants

ECE1 c.139-68C>G Uncertain significance same condition
ECE1 c.1488+1G>A Uncertain significance same condition
ECE1 p.Ala345Ser Uncertain significance ⚠ same condition
ECE1 c.139-43G>A Likely benign same condition
ECE1 p.Gly673= Likely benign same condition
ECE1 p.Pro8= Benign same condition
ECE1 p.Thr354Ala Benign same condition
ECE1 p.Thr312Met 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/ece1-p-arg618gln (accessed [today's date]).

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