Is PGAP1 p.Arg250His (c.749G>A) pathogenic?

PGAP1 p.Arg250His (c.749G>A) is classified Uncertain significance in PGAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-18). AlphaMissense: ambiguous (0.4448); Very rare (popmax 0.00534%, afr); Associated with intellectual disability, autosomal recessive 42.

What condition is associated with PGAP1 p.Arg250His (c.749G>A)?

PGAP1 p.Arg250His (c.749G>A) is associated with intellectual disability, autosomal recessive 42 (ClinVar).

How common is PGAP1 p.Arg250His (c.749G>A) in the general population?

PGAP1 p.Arg250His (c.749G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about PGAP1 p.Arg250His (c.749G>A)?

AlphaMissense predicts ambiguous (score 0.4448) — an in-silico prediction, not a clinical call.

PGAP1 p.Arg250His

c.749G>A · rs764146325 · VCV1984495

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4448 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

intellectual disability, autosomal recessive 42

Computational evidence

Protein change
AlphaMissense	0.4448	ambiguous
REVEL	0.763	pathogenic-leaning
SaProt	LLR -6.87	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 85 kb · p 0.0064 · regional, not allelic
Overall
CADD	33.0	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 0.00534% African / African-American · 4/74,890 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00167% 27/1,613,480 alleles · very rare exomes 22/1,461,346 · genomes 5/152,134 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,722
East Asian	0.00446%	22,433
European (non-Finnish)	0.00161%	62,091
Remaining individualsnot grpmax-eligible	0.0016%	62,460
South Asian	0.0011%	91,000

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.Arg250His
Coding: c.749G>A
MANE Select: NM_024989
dbSNP: rs764146325
Type: single nucleotide variant
Location: chr2:196902643 (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

intellectual disability, autosomal recessive 42 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PGAP1 p.Arg250Pro Uncertain significance ★ ⚠ same residue
PGAP1 p.Gln466Ter Pathogenic ★★ same condition
PGAP1 p.Gln555Ter Pathogenic/Likely pathogenic ★★ same condition
PGAP1 p.Tyr758Ter Pathogenic/Likely pathogenic ★★ same condition
PGAP1 p.Ala298Thr Uncertain significance ★★ ⚠ same condition
PGAP1 p.Ala714Val Uncertain significance ★★ ⚠ same condition
PGAP1 p.Arg231Gln Uncertain significance ★★ ⚠ same condition
PGAP1 p.Arg803Cys 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-arg250his (accessed [today's date]).

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