Is PGAP1 p.Pro861Leu (c.2582C>T) pathogenic?

PGAP1 p.Pro861Leu (c.2582C>T) is classified Uncertain significance in PGAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-29). AlphaMissense: likely benign (0.1484); Very rare (popmax 0.00542%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PGAP1 p.Pro861Leu (c.2582C>T)?

PGAP1 p.Pro861Leu (c.2582C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PGAP1 p.Pro861Leu (c.2582C>T) in the general population?

PGAP1 p.Pro861Leu (c.2582C>T) is very rare (popmax 0.00542%, nfe) (gnomAD).

What do computational predictors say about PGAP1 p.Pro861Leu (c.2582C>T)?

AlphaMissense predicts likely benign (score 0.1484) — an in-silico prediction, not a clinical call.

PGAP1 p.Pro861Leu

c.2582C>T · VCV3359526

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1484 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00542%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1484	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -10.01	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 85 kb · p 0.0064 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00542% European (non-Finnish) · 63/1,161,878 alleles

Filtering AF 0.00433% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00416% 66/1,584,742 alleles · very rare exomes 62/1,433,070 · genomes 4/151,672 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00542%	18,442
East Asian	0.00229%	43,714
Remaining individualsnot grpmax-eligible	0.00163%	61,188
African / African-American	0.00136%	73,728

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.Pro861Leu
Coding: c.2582C>T
MANE Select: NM_024989
Type: single nucleotide variant
Location: chr2:196842769 (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

PGAP1 p.Ala298Thr Uncertain significance ★★ ⚠ same condition
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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

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-pro861leu (accessed [today's date]).

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