Is ECHS1 p.Val47Met (c.139G>A) pathogenic?

ECHS1 p.Val47Met (c.139G>A) is classified Likely pathogenic in ECHS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-16). AlphaMissense: likely pathogenic (0.7283); Very rare (popmax 0.00223%, eas).

How common is ECHS1 p.Val47Met (c.139G>A) in the general population?

ECHS1 p.Val47Met (c.139G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ECHS1 p.Val47Met (c.139G>A)?

AlphaMissense predicts likely pathogenic (score 0.7283) — an in-silico prediction, not a clinical call.

ECHS1 p.Val47Met

c.139G>A · rs761774772 · VCV1929424

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7283 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7283	likely pathogenic ✓ concordant with ClinVar
REVEL	0.627	indeterminate
SaProt	LLR -13.17	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 7.5	phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 10 kb · p 0.4 · regional, not allelic
Overall
CADD	29.5	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 · 1/44,850 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000959% 14/1,460,588 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00314%	31,833
East Asiangrpmax	0.00223%	44,850
European (non-Finnish)	0.000932%	107,247

Finnish 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.Val47Met
Coding: c.139G>A
MANE Select: NM_004092
dbSNP: rs761774772
Type: single nucleotide variant
Location: chr10:133370707 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.54 · 6 PDB
Residue 47: a β-strand

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

Similar variants

ECHS1 p.Val47= Likely benign ★ same residue
ECHS1 c.414+1G>A Pathogenic/Likely pathogenic ★★ same type
ECHS1 c.88+5G>A Pathogenic/Likely pathogenic ★★ same type
ECHS1 p.Ala132Thr Pathogenic/Likely pathogenic ★★ same type
ECHS1 p.Ala173Val Pathogenic/Likely pathogenic ★★ same type
ECHS1 p.Ala238Val Pathogenic/Likely pathogenic ★★ ⚠ same type
ECHS1 p.Ala278Thr Likely pathogenic ★★ same type
ECHS1 p.Ala2Val Pathogenic ★★ same type

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-val47met (accessed [today's date]).

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