Is ENDOG p.Leu179Pro (c.536T>C) pathogenic?

ENDOG p.Leu179Pro (c.536T>C) is classified Uncertain significance in ENDOG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: likely pathogenic (0.9958); Ultra-rare (popmax 0.0825%, mid).

How common is ENDOG p.Leu179Pro (c.536T>C) in the general population?

ENDOG p.Leu179Pro (c.536T>C) is ultra-rare (popmax 0.0825%, mid) (gnomAD).

What do computational predictors say about ENDOG p.Leu179Pro (c.536T>C)?

AlphaMissense predicts likely pathogenic (score 0.9958) — an in-silico prediction, not a clinical call.

ENDOG p.Leu179Pro

c.536T>C · rs528071859 · VCV2471708

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9958 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9958	likely pathogenic · top 2% in ENDOG
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -16.35	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,922 bp · p 0.17 · regional, not allelic
Overall
CADD	32.0	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 0.0825% Middle Eastern · 5/6,060 alleles

Filtering AF 0.0324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00261% 42/1,612,222 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0825%	1,212
Remaining individualsnot grpmax-eligible	0.0112%	8,924
South Asian	0.011%	9,064
Admixed American	0.00335%	29,868
Finnishnot grpmax-eligible	0.00313%	31,931
European (non-Finnish)	0.00136%	73,701

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: ENDOG
Protein: p.Leu179Pro
Coding: c.536T>C
MANE Select: NM_004435
dbSNP: rs528071859
Type: single nucleotide variant
Location: chr9:128820773 (GRCh38)
Gene constraint: LOEUF 1.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.67 · 2 PDB

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

Similar variants

ENDOG p.Arg184Cys Uncertain significance ★★ ⚠ same type
ENDOG p.Ile218= Benign ★★ same type
ENDOG p.Thr246Ile Benign ★★ ⚠ same type
ENDOG p.Ala130Val Uncertain significance ★ ⚠ same type
ENDOG p.Ala143Asp Uncertain significance ★ ⚠ same type
ENDOG p.Ala14Val Uncertain significance ★ ⚠ same type
ENDOG p.Ala252Val Uncertain significance ★ ⚠ same type
ENDOG p.Ala284Val 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/endog-p-leu179pro (accessed [today's date]).

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