Is ECHS1 p.Glu77Lys (c.229G>A) pathogenic?

ECHS1 p.Glu77Lys (c.229G>A) is classified Uncertain significance in ECHS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-17). AlphaMissense: ambiguous (0.4558); Very rare (popmax 0.00223%, eas).

How common is ECHS1 p.Glu77Lys (c.229G>A) in the general population?

ECHS1 p.Glu77Lys (c.229G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ECHS1 p.Glu77Lys (c.229G>A)?

AlphaMissense predicts ambiguous (score 0.4558) — an in-silico prediction, not a clinical call.

ECHS1 p.Glu77Lys

c.229G>A · rs1426014295 · VCV1424044

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4558 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4558	ambiguous
REVEL	0.275	benign-leaning
SaProt	LLR -12.62	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	phastCons 0.93
Regional constraint	o/e 0.96	unconstrained · MANE · 10 kb · p 0.4 · regional, not allelic
Overall
CADD	17.18	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 · 1/44,862 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00143% 23/1,611,848 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,862
European (non-Finnish)	0.00187%	53,612

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.Glu77Lys
Coding: c.229G>A
MANE Select: NM_004092
dbSNP: rs1426014295
Type: single nucleotide variant
Location: chr10:133370617 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.54 · 6 PDB
Residue 77: a UniProt-annotated variant site (in echs1d); an α-helix

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

Similar variants

ECHS1 p.Glu77Gln 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
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-glu77lys (accessed [today's date]).

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