Is ECHS1 p.Ala247Val (c.740C>T) pathogenic?

ECHS1 p.Ala247Val (c.740C>T) is classified Conflicting classifications of pathogenicity in ECHS1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-03-28). AlphaMissense: likely pathogenic (0.6126); Very rare (popmax 0.000254%, nfe); Associated with mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency.

What condition is associated with ECHS1 p.Ala247Val (c.740C>T)?

ECHS1 p.Ala247Val (c.740C>T) is associated with mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency (ClinVar).

How common is ECHS1 p.Ala247Val (c.740C>T) in the general population?

ECHS1 p.Ala247Val (c.740C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ECHS1 p.Ala247Val (c.740C>T)?

AlphaMissense predicts likely pathogenic (score 0.6126) — an in-silico prediction, not a clinical call.

ECHS1 p.Ala247Val

Q: How is Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.740C>T · rs762885546 · VCV802639

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6126 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency

Computational evidence

Protein change
AlphaMissense	0.6126	likely pathogenic
REVEL	0.553	indeterminate
SaProt	LLR -12.33	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.28	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 10 kb · p 0.4 · 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 0.000254% European (non-Finnish) · 3/1,179,184 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,612,958 alleles · very rare

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.Ala247Val
Coding: c.740C>T
MANE Select: NM_004092
dbSNP: rs762885546
Type: single nucleotide variant
Location: chr10:133364725 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.54 · 6 PDB
Residue 247: an α-helix

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

Disease context

mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

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
ECHS1 p.Arg54Cys Pathogenic/Likely 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-ala247val (accessed [today's date]).

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