Is ECHS1 p.Pro22Leu (c.65C>T) pathogenic?

ECHS1 p.Pro22Leu (c.65C>T) is classified Uncertain significance in ECHS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-03). AlphaMissense: likely benign (0.1284); Ultra-rare (popmax 0.0116%, eas).

How common is ECHS1 p.Pro22Leu (c.65C>T) in the general population?

ECHS1 p.Pro22Leu (c.65C>T) is ultra-rare (popmax 0.0116%, eas) (gnomAD).

What do computational predictors say about ECHS1 p.Pro22Leu (c.65C>T)?

AlphaMissense predicts likely benign (score 0.1284) — an in-silico prediction, not a clinical call.

ECHS1 p.Pro22Leu

c.65C>T · rs377287845 · VCV1352310

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1284 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0116%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1284	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.66
Regional constraint	o/e 0.96	unconstrained · MANE · 10 kb · p 0.4 · regional, not allelic
Overall
CADD	9.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0116% East Asian · 4/34,548 alleles

Filtering AF 0.0039% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00232%

Overall 0.000538% 7/1,302,016 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0116%	8,637
Remaining individualsnot grpmax-eligible	0.00355%	28,173
European (non-Finnish)	9e-05%	1,111,496

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.Pro22Leu
Coding: c.65C>T
MANE Select: NM_004092
dbSNP: rs377287845
Type: single nucleotide variant
Location: chr10:133373269 (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

Similar variants

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
ECHS1 p.Arg54Cys Pathogenic/Likely 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-pro22leu (accessed [today's date]).

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