Is ENOX2 p.Pro22Leu (c.65C>T) pathogenic?

ENOX2 p.Pro22Leu (c.65C>T) is classified Uncertain significance in ENOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely pathogenic (0.8286); Very rare (popmax 0.00336%, nfe).

How common is ENOX2 p.Pro22Leu (c.65C>T) in the general population?

ENOX2 p.Pro22Leu (c.65C>T) is very rare (popmax 0.00336%, nfe) (gnomAD).

What do computational predictors say about ENOX2 p.Pro22Leu (c.65C>T)?

AlphaMissense predicts likely pathogenic (score 0.8286) — an in-silico prediction, not a clinical call.

ENOX2 p.Pro22Leu

c.65C>T · VCV4249150

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8286 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00336%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8286	likely pathogenic
REVEL	0.32	indeterminate
SaProt	LLR -9.84	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 47 kb · p 0.0089 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

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 P22L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00336% European (non-Finnish) · 30/892,984 alleles

Filtering AF 0.00238% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00265% 32/1,206,573 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00336%	29,766
Admixed American	0.00219%	45,566
Finnishnot grpmax-eligible	0.00215%	46,595

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: ENOX2
Protein: p.Pro22Leu
Coding: c.65C>T
MANE Select: NM_006375
Type: single nucleotide variant
Location: chrX:130703152 (GRCh38)
Structure: AlphaFold pLDDT 77.86

Full ENOX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENOX2 c.1129+6G>A Benign ★★ same type
ENOX2 c.-38-6023T>G Uncertain significance ★ ⚠ same type
ENOX2 p.Arg129His Uncertain significance ★ ⚠ same type
ENOX2 p.Arg139His Uncertain significance ★ ⚠ same type
ENOX2 p.Arg156His Uncertain significance ★ ⚠ same type
ENOX2 p.Arg190His Uncertain significance ★ ⚠ same type
ENOX2 p.Arg190Leu Uncertain significance ★ ⚠ same type
ENOX2 p.Arg208His 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/enox2-p-pro22leu (accessed [today's date]).

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