Is ECH1 p.Arg185Gln (c.554G>A) pathogenic?

ECH1 p.Arg185Gln (c.554G>A) is classified Uncertain significance in ECH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-16). AlphaMissense: likely pathogenic (0.6878); Ultra-rare (popmax 0.0164%, amr).

How common is ECH1 p.Arg185Gln (c.554G>A) in the general population?

ECH1 p.Arg185Gln (c.554G>A) is ultra-rare (popmax 0.0164%, amr) (gnomAD).

What do computational predictors say about ECH1 p.Arg185Gln (c.554G>A)?

AlphaMissense predicts likely pathogenic (score 0.6878) — an in-silico prediction, not a clinical call.

ECH1 p.Arg185Gln

c.554G>A · VCV3843288

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6878 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6878	likely pathogenic
REVEL	0.486	indeterminate
SaProt	LLR -14.68	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 16 kb · p 0.49 · regional, not allelic
Overall
CADD	33.0	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 0.0164% Admixed American · 9/54,986 alleles

Filtering AF 0.00847% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00635%

Overall 0.00152% 24/1,577,484 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0164%	6,110
Remaining individualsnot grpmax-eligible	0.00654%	15,293
African / African-American	0.00136%	73,740
South Asian	0.00117%	85,704
European (non-Finnish)	0.000775%	129,109

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: ECH1
Protein: p.Arg185Gln
Coding: c.554G>A
MANE Select: NM_001398
Type: single nucleotide variant
Location: chr19:38817099 (GRCh38)
Gene constraint: LOEUF 1.083 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 2 PDB
Residue 185: a β-strand

Full ECH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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ECH1 p.Ala259Thr Uncertain significance ★ ⚠ same type
ECH1 p.Ala3Thr Uncertain significance ★ ⚠ same type
ECH1 p.Ala50Thr Uncertain significance ★ ⚠ same type
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ECH1 p.Arg143His 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/ech1-p-arg185gln (accessed [today's date]).

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