Is PGAP1 p.Leu838Pro (c.2513T>C) pathogenic?

PGAP1 p.Leu838Pro (c.2513T>C) is classified Uncertain significance in PGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-29). AlphaMissense: likely pathogenic (0.6849); Very rare (popmax 0.00191%, amr); Associated with Inborn genetic diseases.

What condition is associated with PGAP1 p.Leu838Pro (c.2513T>C)?

PGAP1 p.Leu838Pro (c.2513T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PGAP1 p.Leu838Pro (c.2513T>C) in the general population?

PGAP1 p.Leu838Pro (c.2513T>C) is very rare (popmax 0.00191%, amr) (gnomAD).

What do computational predictors say about PGAP1 p.Leu838Pro (c.2513T>C)?

AlphaMissense predicts likely pathogenic (score 0.6849) — an in-silico prediction, not a clinical call.

PGAP1 p.Leu838Pro

c.2513T>C · rs1700484639 · VCV2304635

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6849 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00191%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6849	likely pathogenic
REVEL	0.609	indeterminate
SaProt	LLR -11.83	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 85 kb · p 0.0064 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00191% Admixed American · 1/52,298 alleles

Overall 6.57e-05% 1/1,521,074 alleles · very rare exomes 0/1,368,854 · genomes 1/152,220 · 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.Leu838Pro
Coding: c.2513T>C
MANE Select: NM_024989
dbSNP: rs1700484639
Type: single nucleotide variant
Location: chr2:196843900 (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

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-leu838pro (accessed [today's date]).

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