Is ECHS1 p.Asn59Ser (c.176A>G) pathogenic?

ECHS1 p.Asn59Ser (c.176A>G) is classified Pathogenic/Likely pathogenic in ECHS1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-04-23). AlphaMissense: likely pathogenic (0.6589); Rare (popmax 0.105%, eas); Associated with ECHS1-related disorders.

What condition is associated with ECHS1 p.Asn59Ser (c.176A>G)?

ECHS1 p.Asn59Ser (c.176A>G) is associated with ECHS1-related disorders, mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency (ClinVar).

How common is ECHS1 p.Asn59Ser (c.176A>G) in the general population?

ECHS1 p.Asn59Ser (c.176A>G) is rare (popmax 0.105%, eas) (gnomAD).

What do computational predictors say about ECHS1 p.Asn59Ser (c.176A>G)?

AlphaMissense predicts likely pathogenic (score 0.6589) — an in-silico prediction, not a clinical call.

ECHS1 p.Asn59Ser

c.176A>G · rs201865375 · VCV218890

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.6589 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ECHS1-related disorders

Computational evidence

Protein change
AlphaMissense	0.6589	likely pathogenic ✓ concordant with ClinVar
REVEL	0.712	pathogenic-leaning
SaProt	LLR -12.88	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 10 kb · p 0.4 · regional, not allelic
Overall
CADD	24.9	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 0.105% East Asian · 47/44,880 alleles

Filtering AF 0.0808% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0725%

Overall 0.00496% 80/1,613,442 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.105%	955
South Asian	0.00879%	11,381
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
European (non-Finnish)	0.00195%	51,299
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Asn59Ser
Coding: c.176A>G
MANE Select: NM_004092
dbSNP: rs201865375
Type: single nucleotide variant
Location: chr10:133370670 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.54 · 6 PDB
Residue 59: a UniProt-annotated variant site (in echs1d; decreases significantly enoyl-coa hydratase activity; decreases significantly protein expression); 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 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-asn59ser (accessed [today's date]).

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