Is ECHS1 p.Phe76Cys (c.227T>G) pathogenic?

ECHS1 p.Phe76Cys (c.227T>G) is classified Uncertain significance in ECHS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-10-03). AlphaMissense: ambiguous (0.5108); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ECHS1 p.Phe76Cys (c.227T>G)?

ECHS1 p.Phe76Cys (c.227T>G) is associated with Inborn genetic diseases (ClinVar).

How common is ECHS1 p.Phe76Cys (c.227T>G) in the general population?

ECHS1 p.Phe76Cys (c.227T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ECHS1 p.Phe76Cys (c.227T>G)?

AlphaMissense predicts ambiguous (score 0.5108) — an in-silico prediction, not a clinical call.

ECHS1 p.Phe76Cys

c.227T>G · rs1554886473 · VCV522021

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5108 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5108	ambiguous
REVEL	0.514	indeterminate
SaProt	LLR -11.27	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 10 kb · p 0.4 · regional, not allelic
Overall
CADD	23.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ECHS1
Protein: p.Phe76Cys
Coding: c.227T>G
MANE Select: NM_004092
dbSNP: rs1554886473
Type: single nucleotide variant
Location: chr10:133370619 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.54 · 6 PDB
Residue 76: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ECHS1 p.Phe76= Benign ★★ same residue
ECHS1 p.Lys273Glu Pathogenic/Likely pathogenic ★★ ⚠ same condition
ECHS1 p.Ala230Ser Uncertain significance ★★ ⚠ same condition
ECHS1 p.Ala28Ser Uncertain significance ★★ ⚠ same condition
ECHS1 p.Asn245Ser Uncertain significance ★★ ⚠ same condition
ECHS1 p.Gly13Asp Uncertain significance ★★ ⚠ same condition
ECHS1 p.Ile165Val Uncertain significance ★★ ⚠ same condition
ECHS1 p.Ile37Thr Uncertain significance ★★ ⚠ 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-phe76cys (accessed [today's date]).

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