Is ECH1 p.Arg230Cys (c.688C>T) pathogenic?

ECH1 p.Arg230Cys (c.688C>T) is classified Uncertain significance in ECH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-24). AlphaMissense: ambiguous (0.491); Very rare (popmax 0.00401%, afr).

How common is ECH1 p.Arg230Cys (c.688C>T) in the general population?

ECH1 p.Arg230Cys (c.688C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about ECH1 p.Arg230Cys (c.688C>T)?

AlphaMissense predicts ambiguous (score 0.491) — an in-silico prediction, not a clinical call.

ECH1 p.Arg230Cys

c.688C>T · rs745972137 · VCV2296248

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.491 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Computational evidence

Protein change
AlphaMissense	0.491	ambiguous
REVEL	0.628	indeterminate
SaProt	LLR -15.16	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,880 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00105% 17/1,613,632 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,960
East Asian	0.00223%	44,886
European (non-Finnish)	0.0011%	90,768

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.Arg230Cys
Coding: c.688C>T
MANE Select: NM_001398
dbSNP: rs745972137
Type: single nucleotide variant
Location: chr19:38816327 (GRCh38)
Gene constraint: LOEUF 1.083 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 2 PDB

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

Similar variants

ECH1 p.Arg230His Uncertain significance ★ ⚠ same residue
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

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-arg230cys (accessed [today's date]).

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