Is ECHS1 p.Ala238Pro (c.712G>C) pathogenic?

ECHS1 p.Ala238Pro (c.712G>C) is classified Conflicting classifications of pathogenicity in ECHS1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-12). AlphaMissense: likely pathogenic (0.8371); Very rare (popmax 0.00667%, amr).

How common is ECHS1 p.Ala238Pro (c.712G>C) in the general population?

ECHS1 p.Ala238Pro (c.712G>C) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about ECHS1 p.Ala238Pro (c.712G>C)?

AlphaMissense predicts likely pathogenic (score 0.8371) — an in-silico prediction, not a clinical call.

ECHS1 p.Ala238Pro

c.712G>C · rs142639185 · VCV1488259

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8371 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8371	likely pathogenic
REVEL	0.424	indeterminate
SaProt	LLR -11.59	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.39	phastCons 0.017
Regional constraint	o/e 0.96	unconstrained · MANE · 10 kb · p 0.4 · regional, not allelic
Overall
CADD	19.64	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 0.00667% Admixed American · 4/60,012 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00031% 5/1,613,884 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,003
European (non-Finnish)	8.47e-05%	1,180,040

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.Ala238Pro
Coding: c.712G>C
MANE Select: NM_004092
dbSNP: rs142639185
Type: single nucleotide variant
Location: chr10:133366003 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.54 · 6 PDB
Residue 238: an α-helix

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

Similar variants

ECHS1 p.Ala238Val Pathogenic/Likely pathogenic ★★ ⚠ same residue
ECHS1 p.Ala238Thr Likely 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.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-ala238pro (accessed [today's date]).

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