Is ECHS1 p.Ser256Arg (c.768T>G) pathogenic?

ECHS1 p.Ser256Arg (c.768T>G) is classified Uncertain significance in ECHS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-22). AlphaMissense: likely pathogenic (0.5963); Absent from gnomAD v4.1.

How common is ECHS1 p.Ser256Arg (c.768T>G) in the general population?

ECHS1 p.Ser256Arg (c.768T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ECHS1 p.Ser256Arg (c.768T>G)?

AlphaMissense predicts likely pathogenic (score 0.5963) — an in-silico prediction, not a clinical call.

ECHS1 p.Ser256Arg

c.768T>G · rs2133438742 · VCV1495331

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5963 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5963	likely pathogenic
REVEL	0.113	moderately benign-leaning
SaProt	LLR -7.17	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.62	donor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.92
Regional constraint	o/e 0.96	unconstrained · MANE · 10 kb · p 0.4 · regional, not allelic
Overall
CADD	8.079	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.Ser256Arg
Coding: c.768T>G
MANE Select: NM_004092
dbSNP: rs2133438742
Type: single nucleotide variant
Location: chr10:133364697 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.54 · 6 PDB
Residue 256: an α-helix

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

Similar variants

ECHS1 p.Ser256Asn Uncertain significance ★ ⚠ 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-ser256arg (accessed [today's date]).

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