Is ECHS1 p.Tyr137fs (c.410_411del) pathogenic?

ECHS1 p.Tyr137fs (c.410411del) is classified Conflicting classifications of pathogenicity in ECHS1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-23). Ultra-rare (popmax 0.0427%, afr); Associated with ECHS1-related disorders.

What condition is associated with ECHS1 p.Tyr137fs (c.410_411del)?

ECHS1 p.Tyr137fs (c.410_411del) is associated with ECHS1-related disorders, mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency (ClinVar).

How common is ECHS1 p.Tyr137fs (c.410_411del) in the general population?

ECHS1 p.Tyr137fs (c.410_411del) is ultra-rare (popmax 0.0427%, afr) (gnomAD).

ECHS1 p.Tyr137fs

c.410_411del · rs777218310 · VCV418830

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0427%, afr)

Conditions

ECHS1-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.5	phastCons 1
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0427% African / African-American · 32/74,942 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0271%

Overall 0.00229% 37/1,613,352 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0427%	2,342
Remaining individualsnot grpmax-eligible	0.00641%	15,611
European (non-Finnish)	8.48e-05%	1,179,912

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: ECHS1
Protein: p.Tyr137fs
Coding: c.410_411del
MANE Select: NM_004092
dbSNP: rs777218310
Type: Deletion
Location: chr10:133369907 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.54 · 6 PDB
Residue 137: a β-strand

Full ECHS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ECHS1-related disorders

Also linked: mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency

Similar variants

ECHS1 p.Asp202fs Likely pathogenic ★ same condition
ECHS1 c.414+1G>A Pathogenic/Likely pathogenic ★★ same condition
ECHS1 c.88+5G>A Pathogenic/Likely pathogenic ★★ same condition
ECHS1 p.Ala132Thr Pathogenic/Likely pathogenic ★★ same condition
ECHS1 p.Ala173Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
ECHS1 p.Ala238Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
ECHS1 p.Ala278Thr Likely pathogenic ★★ same condition
ECHS1 p.Ala2Val Pathogenic ★★ ⚠ same condition

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/echs1-p-tyr137fs (accessed [today's date]).

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