Is ECHDC1 p.Pro45Leu (c.134C>T) pathogenic?

ECHDC1 p.Pro45Leu (c.134C>T) is classified Uncertain significance in ECHDC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely benign (0.0967); Ultra-rare (popmax 0.016%, afr).

How common is ECHDC1 p.Pro45Leu (c.134C>T) in the general population?

ECHDC1 p.Pro45Leu (c.134C>T) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about ECHDC1 p.Pro45Leu (c.134C>T)?

AlphaMissense predicts likely benign (score 0.0967) — an in-silico prediction, not a clinical call.

ECHDC1 p.Pro45Leu

c.134C>T · VCV4016017

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0967 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0967	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -9.39	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 8.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 41 kb · p 0.24 · regional, not allelic
Overall
CADD	23.0	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P51L vs ClinVar P45L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% African / African-American · 12/74,906 alleles

Filtering AF 0.00922% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.00428% 69/1,613,978 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,242
European (non-Finnish)	0.00466%	21,455
East Asian	0.00223%	44,862
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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: ECHDC1
Protein: p.Pro45Leu
Coding: c.134C>T
MANE Select: NM_001002030
Type: single nucleotide variant
Location: chr6:127330895 (GRCh38)
Gene constraint: LOEUF 1.452 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.84

Full ECHDC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ECHDC1 p.Met130Thr Likely pathogenic ★ same type
ECHDC1 c.-3+979G>C Uncertain significance ★ ⚠ same type
ECHDC1 p.Ala101Val Uncertain significance ★ ⚠ same type
ECHDC1 p.Ala272Thr Uncertain significance ★ ⚠ same type
ECHDC1 p.Arg192Gln Uncertain significance ★ ⚠ same type
ECHDC1 p.Arg99His Uncertain significance ★ ⚠ same type
ECHDC1 p.Cys262Phe Uncertain significance ★ ⚠ same type
ECHDC1 p.Gln228His Uncertain significance ★ ⚠ 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/echdc1-p-pro45leu (accessed [today's date]).

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