Is ECHS1 p.Gly175Ser (c.523G>A) pathogenic?

ECHS1 p.Gly175Ser (c.523G>A) is classified Conflicting classifications of pathogenicity in ECHS1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-04-21). AlphaMissense: likely pathogenic (0.6764); Very rare (popmax 0.00223%, eas); Associated with ECHS1-related disorders.

What condition is associated with ECHS1 p.Gly175Ser (c.523G>A)?

ECHS1 p.Gly175Ser (c.523G>A) is associated with ECHS1-related disorders, mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency (ClinVar).

How common is ECHS1 p.Gly175Ser (c.523G>A) in the general population?

ECHS1 p.Gly175Ser (c.523G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ECHS1 p.Gly175Ser (c.523G>A)?

AlphaMissense predicts likely pathogenic (score 0.6764) — an in-silico prediction, not a clinical call.

ECHS1 p.Gly175Ser

c.523G>A · rs962504241 · VCV1300726

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6764 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ECHS1-related disorders

Computational evidence

Protein change
AlphaMissense	0.6764	likely pathogenic
REVEL	0.626	indeterminate
SaProt	LLR -13.64	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 10 kb · p 0.4 · regional, not allelic
Overall
CADD	26.5	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 0.00223% East Asian · 1/44,832 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000559% 9/1,610,854 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594
Finnishnot grpmax-eligible	0.00323%	30,979
East Asiangrpmax	0.00223%	44,832
European (non-Finnish)	0.000424%	235,917

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gly175Ser
Coding: c.523G>A
MANE Select: NM_004092
dbSNP: rs962504241
Type: single nucleotide variant
Location: chr10:133366985 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.54 · 6 PDB

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-gly175ser (accessed [today's date]).

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