Is PGAP3 p.Val280Ala (c.839T>C) pathogenic?

PGAP3 p.Val280Ala (c.839T>C) is classified Uncertain significance in PGAP3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-18). AlphaMissense: ambiguous (0.3652); Very rare (popmax 0.00169%, amr); Associated with Inborn genetic diseases.

What condition is associated with PGAP3 p.Val280Ala (c.839T>C)?

PGAP3 p.Val280Ala (c.839T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PGAP3 p.Val280Ala (c.839T>C) in the general population?

PGAP3 p.Val280Ala (c.839T>C) is very rare (popmax 0.00169%, amr) (gnomAD).

What do computational predictors say about PGAP3 p.Val280Ala (c.839T>C)?

AlphaMissense predicts ambiguous (score 0.3652) — an in-silico prediction, not a clinical call.

PGAP3 p.Val280Ala

c.839T>C · rs1044944497 · VCV1445592

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3652 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3652	ambiguous
REVEL	0.176	moderately benign-leaning
SaProt	LLR -8.25	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 15 kb · p 0.63 · regional, not allelic
Overall
CADD	26.2	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 0.00169% Admixed American · 1/59,032 alleles

Overall 0.000497% 8/1,608,970 alleles · very rare exomes 6/1,456,728 · genomes 2/152,242 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0112%	8,909
Admixed Americangrpmax	0.00169%	59,032

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PGAP3
Protein: p.Val280Ala
Coding: c.839T>C
MANE Select: NM_033419
dbSNP: rs1044944497
Type: single nucleotide variant
Location: chr17:39673111 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.17

Full PGAP3 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

PGAP3 p.Glu37Ter Pathogenic ★★ same condition
PGAP3 p.Arg126Cys Uncertain significance ★★ ⚠ same condition
PGAP3 p.Gly84Asp Uncertain significance ★★ ⚠ same condition
PGAP3 p.Thr161Ile Uncertain significance ★★ same condition
PGAP3 p.Val145Ala Uncertain significance ★★ same condition
PGAP3 p.Val211Asp Uncertain significance ★★ ⚠ same condition
PGAP3 p.Val253Met Uncertain significance ★★ ⚠ same condition
PGAP3 p.Arg248Gln Likely benign ★★ 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/pgap3-p-val280ala (accessed [today's date]).

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