Is ENOX2 p.Met1Val (c.1A>G) pathogenic?

ENOX2 p.Met1Val (c.1A>G) is classified Uncertain significance in ENOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.0629); Ultra-rare (popmax 0.0769%, afr).

How common is ENOX2 p.Met1Val (c.1A>G) in the general population?

ENOX2 p.Met1Val (c.1A>G) is ultra-rare (popmax 0.0769%, afr) (gnomAD).

What do computational predictors say about ENOX2 p.Met1Val (c.1A>G)?

AlphaMissense predicts likely benign (score 0.0629) — an in-silico prediction, not a clinical call.

ENOX2 p.Met1Val

c.1A>G · VCV4249145

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0629 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0769%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0629	likely benign
Consequence	start-loss	predicted loss-of-function
REVEL	0.429	indeterminate
SaProt	LLR -6.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.2, phastCons 1
Overall
CADD	15.69	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. Predicted loss-of-function is descriptive, not an applied PVS1 code.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM M30V vs ClinVar M1V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0769% African / African-American · 44/57,202 alleles

Filtering AF 0.0589% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0524%

Overall 0.00408% 49/1,202,111 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0769%	1,300
Admixed American	0.00442%	22,611
Remaining individualsnot grpmax-eligible	0.00423%	23,661
European (non-Finnish)	0.000112%	890,107

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.Met1Val
Coding: c.1A>G
MANE Select: NM_006375
Type: single nucleotide variant
Location: chrX:130703216 (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-met1val (accessed [today's date]).

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