Is ECHS1 p.Ser9Phe (c.26C>T) pathogenic?

ECHS1 p.Ser9Phe (c.26C>T) is classified Uncertain significance in ECHS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.1267); Very rare (popmax 0.0021%, amr); Associated with Inborn genetic diseases.

What condition is associated with ECHS1 p.Ser9Phe (c.26C>T)?

ECHS1 p.Ser9Phe (c.26C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ECHS1 p.Ser9Phe (c.26C>T) in the general population?

ECHS1 p.Ser9Phe (c.26C>T) is very rare (popmax 0.0021%, amr) (gnomAD).

What do computational predictors say about ECHS1 p.Ser9Phe (c.26C>T)?

AlphaMissense predicts likely benign (score 0.1267) — an in-silico prediction, not a clinical call.

ECHS1 p.Ser9Phe

c.26C>T · VCV4246371

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1267 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0021%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1267	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -10.92	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.81
Regional constraint	o/e 0.96	unconstrained · MANE · 10 kb · p 0.4 · regional, not allelic
Overall
CADD	11.56	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 0.0021% Admixed American · 1/47,526 alleles

Filtering AF 7.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000266% 4/1,501,560 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0021%	47,526
European (non-Finnish)	0.000265%	377,017

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.Ser9Phe
Coding: c.26C>T
MANE Select: NM_004092
Type: single nucleotide variant
Location: chr10:133373308 (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

Disease context

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

Similar variants

ECHS1 p.Ser9= Likely 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-ser9phe (accessed [today's date]).

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