Is PGAP1 p.Ser139Asn (c.416G>A) pathogenic?

PGAP1 p.Ser139Asn (c.416G>A) is classified Uncertain significance in PGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-24). AlphaMissense: ambiguous (0.4894); Rare (popmax 0.115%, mid); Associated with intellectual disability, autosomal recessive 42.

What condition is associated with PGAP1 p.Ser139Asn (c.416G>A)?

PGAP1 p.Ser139Asn (c.416G>A) is associated with intellectual disability, autosomal recessive 42 (ClinVar).

How common is PGAP1 p.Ser139Asn (c.416G>A) in the general population?

PGAP1 p.Ser139Asn (c.416G>A) is rare (popmax 0.115%, mid) (gnomAD).

What do computational predictors say about PGAP1 p.Ser139Asn (c.416G>A)?

AlphaMissense predicts ambiguous (score 0.4894) — an in-silico prediction, not a clinical call.

PGAP1 p.Ser139Asn

c.416G>A · rs201030311 · VCV2189618

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4894 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

intellectual disability, autosomal recessive 42

Computational evidence

Protein change
AlphaMissense	0.4894	ambiguous
REVEL	0.079	moderately benign-leaning
SaProt	LLR -5.79	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 85 kb · p 0.0064 · regional, not allelic
Overall
CADD	22.2	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 0.115% Middle Eastern · 7/6,066 alleles

Filtering AF 0.0541% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0384%

Overall 0.00155% 25/1,613,474 alleles · rare exomes 24/1,461,272 · genomes 1/152,202 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	867
Remaining individualsnot grpmax-eligible	0.00961%	10,410
Admixed American	0.00834%	11,988
South Asian	0.0011%	91,034
European (non-Finnish)	0.000509%	196,634

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.Ser139Asn
Coding: c.416G>A
MANE Select: NM_024989
dbSNP: rs201030311
Type: single nucleotide variant
Location: chr2:196916479 (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.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.Arg250His 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-ser139asn (accessed [today's date]).

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