Is ECEL1 p.Leu733Pro (c.2198T>C) pathogenic?

ECEL1 p.Leu733Pro (c.2198T>C) is classified Uncertain significance in ECEL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). AlphaMissense: likely pathogenic (0.983); Very rare (popmax 0.00356%, nfe); Associated with ECEL1-related disorder.

What condition is associated with ECEL1 p.Leu733Pro (c.2198T>C)?

ECEL1 p.Leu733Pro (c.2198T>C) is associated with ECEL1-related disorder (ClinVar).

How common is ECEL1 p.Leu733Pro (c.2198T>C) in the general population?

ECEL1 p.Leu733Pro (c.2198T>C) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about ECEL1 p.Leu733Pro (c.2198T>C)?

AlphaMissense predicts likely pathogenic (score 0.983) — an in-silico prediction, not a clinical call.

ECEL1 p.Leu733Pro

c.2198T>C · rs139624409 · VCV2635911

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.983 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ECEL1-related disorder

Computational evidence

Protein change
AlphaMissense	0.983	likely pathogenic · top 9% in ECEL1
REVEL	0.858	moderately pathogenic-leaning
SaProt	LLR -12.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 6,497 bp · p 0.15 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00356% European (non-Finnish) · 42/1,179,996 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00266% 43/1,613,866 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,095
African / African-American	0.00133%	74,924

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: ECEL1
Protein: p.Leu733Pro
Coding: c.2198T>C
MANE Select: NM_004826
dbSNP: rs139624409
Type: single nucleotide variant
Location: chr2:232480429 (GRCh38)
Gene constraint: LOEUF 1.099 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.62
Residue 733: a disulfide bond; the peptidase m13 domain

Full ECEL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ECEL1-related disorder

Similar variants

ECEL1 p.Gln435Ter Pathogenic/Likely pathogenic ★★ same condition
ECEL1 p.Thr615Pro Likely pathogenic ★ same condition
ECEL1 p.Tyr618Ter Likely pathogenic ★ same condition
ECEL1 p.Val385= Likely pathogenic ★ same condition
ECEL1 p.Arg404Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
ECEL1 p.Arg663Trp Uncertain significance ⚠ same condition
ECEL1 c.2228+4T>A Likely benign same condition
ECEL1 p.Ala493= Likely benign 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/ecel1-p-leu733pro (accessed [today's date]).

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