Is ECEL1 p.Thr46Pro (c.136A>C) pathogenic?

ECEL1 p.Thr46Pro (c.136A>C) is classified Uncertain significance in ECEL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: likely benign (0.0391); Very rare (popmax 0.00189%, sas); Associated with Inborn genetic diseases.

What condition is associated with ECEL1 p.Thr46Pro (c.136A>C)?

ECEL1 p.Thr46Pro (c.136A>C) is associated with Inborn genetic diseases (ClinVar).

How common is ECEL1 p.Thr46Pro (c.136A>C) in the general population?

ECEL1 p.Thr46Pro (c.136A>C) is very rare (popmax 0.00189%, sas) (gnomAD).

What do computational predictors say about ECEL1 p.Thr46Pro (c.136A>C)?

AlphaMissense predicts likely benign (score 0.0391) — an in-silico prediction, not a clinical call.

ECEL1 p.Thr46Pro

c.136A>C · rs2469653169 · VCV2358907

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0391 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00189%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0391	likely benign
REVEL	0.272	benign-leaning
SaProt	LLR -4.21	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 -9.2	GERP -1.9
Regional constraint	o/e 0.96	unconstrained · MANE · 6,497 bp · p 0.15 · regional, not allelic
Overall
CADD	0.001	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 0.00189% South Asian · 1/52,870 alleles

Filtering AF 3.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.2e-05%

Overall 0.000336% 4/1,190,510 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00277%	36,150
South Asiangrpmax	0.00189%	52,870
European (non-Finnish)	0.000189%	528,854

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr46Pro
Coding: c.136A>C
MANE Select: NM_004826
dbSNP: rs2469653169
Type: single nucleotide variant
Location: chr2:232486518 (GRCh38)
Gene constraint: LOEUF 1.099 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.62

Full ECEL1 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

ECEL1 p.Thr46Asn Uncertain significance ★ ⚠ same residue
ECEL1 p.Arg756Trp Uncertain significance ★★ ⚠ same condition
ECEL1 p.Gly209Val Uncertain significance ★★ ⚠ same condition
ECEL1 p.Pro34Ser Uncertain significance ★★ ⚠ same condition
ECEL1 p.Ser44Arg Uncertain significance ★★ ⚠ same condition
ECEL1 p.Arg355Gln Likely benign ★★ same condition
ECEL1 c.1990-6C>T Conflicting classifications of pathogenicity ★ same condition
ECEL1 p.Ala109Val 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/ecel1-p-thr46pro (accessed [today's date]).

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