Is ECHS1 p.Met1Val (c.1A>G) pathogenic?

ECHS1 p.Met1Val (c.1A>G) is classified Pathogenic in ECHS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). Ultra-rare (popmax 0.0184%, sas).

How common is ECHS1 p.Met1Val (c.1A>G) in the general population?

ECHS1 p.Met1Val (c.1A>G) is ultra-rare (popmax 0.0184%, sas) (gnomAD).

ECHS1 p.Met1Val

c.1A>G · rs753557738 · VCV1382291

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0184%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.342	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	phastCons 1
Overall
CADD	19.44	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0184% South Asian · 15/81,588 alleles

Filtering AF 0.0113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00912%

Overall 0.00163% 22/1,350,242 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0184%	5,439
East Asian	0.00567%	17,627
Remaining individualsnot grpmax-eligible	0.00342%	29,226
European (non-Finnish)	0.000265%	377,314

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.Met1Val
Coding: c.1A>G
MANE Select: NM_004092
dbSNP: rs753557738
Type: single nucleotide variant
Location: chr10:133373333 (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

Similar variants

ECHS1 p.Met1Arg Pathogenic/Likely pathogenic ★★ same residue
ECHS1 p.Met1Ile Pathogenic ★ same residue
ECHS1 p.Met1Thr Pathogenic ★ 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

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-met1val (accessed [today's date]).

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