Is ECH1 p.Arg137Trp (c.409C>T) pathogenic?

ECH1 p.Arg137Trp (c.409C>T) is classified Uncertain significance in ECH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: ambiguous (0.3956); Very rare (popmax 0.00891%, eas).

How common is ECH1 p.Arg137Trp (c.409C>T) in the general population?

ECH1 p.Arg137Trp (c.409C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about ECH1 p.Arg137Trp (c.409C>T)?

AlphaMissense predicts ambiguous (score 0.3956) — an in-silico prediction, not a clinical call.

ECH1 p.Arg137Trp

c.409C>T · VCV4838124

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3956 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Computational evidence

Protein change
AlphaMissense	0.3956	ambiguous
REVEL	0.479	indeterminate
SaProt	LLR -15.21	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 16 kb · p 0.49 · regional, not allelic
Overall
CADD	32.0	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 0.00891% East Asian · 4/44,886 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000744% 12/1,613,808 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,222
Admixed American	0.00167%	59,974
South Asian	0.0011%	91,058
European (non-Finnish)	0.000509%	196,652

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.Arg137Trp
Coding: c.409C>T
MANE Select: NM_001398
Type: single nucleotide variant
Location: chr19:38817516 (GRCh38)
Gene constraint: LOEUF 1.083 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 2 PDB
Residue 137: an α-helix

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

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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
ECH1 p.Arg143His Uncertain significance ★ ⚠ same type
ECH1 p.Arg185Gln 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-arg137trp (accessed [today's date]).

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