Is ECHS1 p.Ala2Val (c.5C>T) pathogenic?

ECHS1 p.Ala2Val (c.5C>T) is classified Pathogenic in ECHS1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-11-12). AlphaMissense: ambiguous (0.3612); Very rare (popmax 0.00849%, eas); Associated with mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency.

What condition is associated with ECHS1 p.Ala2Val (c.5C>T)?

ECHS1 p.Ala2Val (c.5C>T) is associated with mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency, Leigh syndrome (ClinVar).

How common is ECHS1 p.Ala2Val (c.5C>T) in the general population?

ECHS1 p.Ala2Val (c.5C>T) is very rare (popmax 0.00849%, eas) (gnomAD).

What do computational predictors say about ECHS1 p.Ala2Val (c.5C>T)?

AlphaMissense predicts ambiguous (score 0.3612) — an in-silico prediction, not a clinical call.

ECHS1 p.Ala2Val

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.5C>T · rs587776498 · VCV156434

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.3612 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00849%, eas)

Conditions

mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency

Computational evidence

Protein change
AlphaMissense	0.3612	ambiguous
REVEL	0.604	indeterminate
SaProt	LLR -10.99	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 10 kb · p 0.4 · regional, not allelic
Overall
CADD	23.0	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 0.00849% East Asian · 3/35,330 alleles

Filtering AF 0.00258% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00227%

Overall 0.00306% 46/1,502,630 alleles · very rare exomes 40/1,350,540 · genomes 6/152,090 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00849%	11,777
European (non-Finnish)	0.00345%	29,025
African / African-American	0.00289%	34,588
Finnishnot grpmax-eligible	0.00222%	45,130
Remaining individualsnot grpmax-eligible	0.00171%	58,424

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.Ala2Val
Coding: c.5C>T
MANE Select: NM_004092
dbSNP: rs587776498
Type: single nucleotide variant
Location: chr10:133373329 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.54 · 6 PDB
Residue 2: a UniProt-annotated variant site (in echs1d)

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

Also linked: Leigh syndrome

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

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

ECHS1 p.Ala2fs Likely pathogenic ★ same residue
ECHS1 p.Ala2Ser Uncertain significance ★ ⚠ same residue
ECHS1 p.Ala2= Likely benign ★ same residue
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

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-ala2val (accessed [today's date]).

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