Is PGAP2 p.Ile253Met (c.759C>G) pathogenic?

PGAP2 p.Ile253Met (c.759C>G) is classified Uncertain significance in PGAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: likely benign (0.1088); Absent from gnomAD v4.1.

How common is PGAP2 p.Ile253Met (c.759C>G) in the general population?

PGAP2 p.Ile253Met (c.759C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PGAP2 p.Ile253Met (c.759C>G)?

AlphaMissense predicts likely benign (score 0.1088) — an in-silico prediction, not a clinical call.

PGAP2 p.Ile253Met

c.759C>G · VCV4701893

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1088 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1088	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -9.33	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 2.8	GERP -0.03, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.023 · regional, not allelic
Overall
CADD	19.2	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I192M vs ClinVar I253M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PGAP2
Protein: p.Ile253Met
Coding: c.759C>G
MANE Select: NM_014489
Type: single nucleotide variant
Location: chr11:3825070 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.00

Full PGAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PGAP2 p.Ala127Val Likely pathogenic ★★ same type
PGAP2 p.Arg238Pro Pathogenic/Likely pathogenic ★★ ⚠ same type
PGAP2 p.Thr294Met Likely pathogenic ★★ same type
PGAP2 c.602-3C>T Uncertain significance ★★ same type
PGAP2 p.Ala187Thr Uncertain significance ★★ ⚠ same type
PGAP2 p.Ala33Thr Uncertain significance ★★ ⚠ same type
PGAP2 p.Arg238Cys Uncertain significance ★★ ⚠ same type
PGAP2 p.Asn205Lys 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/pgap2-p-ile253met (accessed [today's date]).

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