Is ECH1 p.Gly217Arg (c.649G>A) pathogenic?

ECH1 p.Gly217Arg (c.649G>A) is classified Benign in ECH1 (ClinVar, Single submitter, 2 submitters). AlphaMissense: ambiguous (0.4719); Common (popmax 15.9%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ECH1 p.Gly217Arg (c.649G>A)?

AlphaMissense predicts ambiguous (score 0.4719) — an in-silico prediction, not a clinical call.

ECH1 p.Gly217Arg

Q: How common is ECH1 p.Gly217Arg (c.649G>A) in the general population?

ECH1 p.Gly217Arg (c.649G>A) is common (popmax 15.9%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.649G>A · rs2229259 · VCV559111

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4719 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 15.9%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4719	ambiguous
REVEL	0.716	pathogenic-leaning
SaProt	LLR -12.48	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 16 kb · p 0.49 · regional, not allelic
Overall
CADD	28.9	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 15.9% Admixed American · 9,510/59,998 alleles

Filtering AF 15.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 15.5%

Overall 10.1% 163,050/1,614,016 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	15.9%	6
Ashkenazi Jewishnot grpmax-eligible	11%	9
Amishnot grpmax-eligible	10.7%	9
European (non-Finnish)	10.5%	9
Remaining individualsnot grpmax-eligible	10.3%	10
Middle Eastern	9.8%	10
Finnishnot grpmax-eligible	8.82%	11
East Asian	8.76%	11
South Asian	8.36%	12
African / African-American	2.13%	47

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.Gly217Arg
Coding: c.649G>A
MANE Select: NM_001398
dbSNP: rs2229259
Type: single nucleotide variant
Location: chr19:38816463 (GRCh38)
Gene constraint: LOEUF 1.083 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 2 PDB
Residue 217: a UniProt-annotated variant site (in)

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

Similar variants

ECH1 p.Lys95Arg Uncertain significance ★★ ⚠ same type
ECH1 p.Ala226Thr Uncertain significance ★ ⚠ same type
ECH1 p.Ala237Val Uncertain significance ★ ⚠ same type
ECH1 p.Ala259Thr Uncertain significance ★ ⚠ same type
ECH1 p.Ala3Thr Uncertain significance ★ ⚠ same type
ECH1 p.Ala50Thr Uncertain significance ★ ⚠ same type
ECH1 p.Arg137Trp Uncertain significance ★ ⚠ same type
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-gly217arg (accessed [today's date]).

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