Is PGAP1 p.Ala864Val (c.2591C>T) pathogenic?

PGAP1 p.Ala864Val (c.2591C>T) is classified Uncertain significance in PGAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-16). AlphaMissense: likely benign (0.0953); Very rare (popmax 0.000259%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PGAP1 p.Ala864Val (c.2591C>T)?

PGAP1 p.Ala864Val (c.2591C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PGAP1 p.Ala864Val (c.2591C>T) in the general population?

PGAP1 p.Ala864Val (c.2591C>T) is very rare (popmax 0.000259%, nfe) (gnomAD).

What do computational predictors say about PGAP1 p.Ala864Val (c.2591C>T)?

AlphaMissense predicts likely benign (score 0.0953) — an in-silico prediction, not a clinical call.

PGAP1 p.Ala864Val

c.2591C>T · rs749798369 · VCV2663550

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0953 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000259%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0953	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -5.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	donor loss, 39 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.3	GERP 1, phastCons 0.002
Regional constraint	o/e 0.92	unconstrained · MANE · 85 kb · p 0.0064 · regional, not allelic
Overall
CADD	16.13	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000259% European (non-Finnish) · 3/1,160,518 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000189% 3/1,583,768 alleles · very rare exomes 1/1,431,810 · genomes 2/151,958 · joint denominator

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: PGAP1
Protein: p.Ala864Val
Coding: c.2591C>T
MANE Select: NM_024989
dbSNP: rs749798369
Type: single nucleotide variant
Location: chr2:196842760 (GRCh38)
Gene constraint: LOEUF 0.691 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 89.15

Full PGAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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PGAP1 p.Arg803His Uncertain significance ★★ ⚠ same condition
PGAP1 p.Arg814Cys Uncertain significance ★★ ⚠ same condition
PGAP1 p.Asn129Ser Uncertain significance ★★ ⚠ same condition
PGAP1 p.Asn363Asp Uncertain significance ★★ ⚠ same condition
PGAP1 p.His261Tyr Uncertain significance ★★ ⚠ same condition
PGAP1 p.Ile51Met Uncertain significance ★★ ⚠ same condition

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/pgap1-p-ala864val (accessed [today's date]).

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