Is ENDOU p.Leu332Pro (c.995T>C) pathogenic?

ENDOU p.Leu332Pro (c.995T>C) is classified Uncertain significance in ENDOU (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely pathogenic (0.9219); Ultra-rare (popmax 0.0165%, mid).

How common is ENDOU p.Leu332Pro (c.995T>C) in the general population?

ENDOU p.Leu332Pro (c.995T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ENDOU p.Leu332Pro (c.995T>C)?

AlphaMissense predicts likely pathogenic (score 0.9219) — an in-silico prediction, not a clinical call.

ENDOU p.Leu332Pro

c.995T>C · VCV4835989

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9219 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9219	likely pathogenic · top 3% in ENDOU
REVEL	0.605	indeterminate
SaProt	LLR -14.45	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.018 · regional, not allelic
Overall
CADD	26.7	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,614,210 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)	0.000169%	590,016

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: ENDOU
Protein: p.Leu332Pro
Coding: c.995T>C
MANE Select: NM_001172439
Type: single nucleotide variant
Location: chr12:47711753 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.91 · 1 PDB
Residue 332: the endou domain; a β-strand

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

Similar variants

ENDOU p.Arg211Gln Benign ★★ same type
ENDOU p.Asp228= Benign ★★ same type
ENDOU p.Tyr317= Benign ★★ same type
ENDOU c.551+1G>A Uncertain significance ★ same type
ENDOU p.Ala229Val Uncertain significance ★ ⚠ same type
ENDOU p.Ala402Thr Uncertain significance ★ ⚠ same type
ENDOU p.Ala404Pro Uncertain significance ★ ⚠ same type
ENDOU p.Ala78Asp 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/endou-p-leu332pro (accessed [today's date]).

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