Is PGAP1 p.Pro912Ser (c.2734C>T) pathogenic?

PGAP1 p.Pro912Ser (c.2734C>T) is classified Benign/Likely benign in PGAP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-20). AlphaMissense: likely benign (0.1378); Rare (popmax 0.102%, amr); Associated with intellectual disability, autosomal recessive 42.

What condition is associated with PGAP1 p.Pro912Ser (c.2734C>T)?

PGAP1 p.Pro912Ser (c.2734C>T) is associated with intellectual disability, autosomal recessive 42, hereditary spastic paraplegia (ClinVar).

How common is PGAP1 p.Pro912Ser (c.2734C>T) in the general population?

PGAP1 p.Pro912Ser (c.2734C>T) is rare (popmax 0.102%, amr) (gnomAD).

What do computational predictors say about PGAP1 p.Pro912Ser (c.2734C>T)?

AlphaMissense predicts likely benign (score 0.1378) — an in-silico prediction, not a clinical call.

PGAP1 p.Pro912Ser

c.2734C>T · rs147312612 · VCV1164203

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1378 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.102%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal recessive 42

Computational evidence

Protein change
AlphaMissense	0.1378	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -7.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.85, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 85 kb · p 0.0064 · regional, not allelic
Overall
CADD	16.27	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 0.102% Admixed American · 61/59,932 alleles

Filtering AF 0.0812% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0739%

Overall 0.0403% 650/1,613,580 alleles · rare exomes 591/1,461,510 · genomes 59/152,070 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.33%	75
Admixed Americangrpmax	0.102%	982
Remaining individualsnot grpmax-eligible	0.096%	1,041
European (non-Finnish)	0.011%	9,076
African / African-American	0.00668%	14,974
South Asian	0.0011%	91,014

Ashkenazi Jewish 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: PGAP1
Protein: p.Pro912Ser
Coding: c.2734C>T
MANE Select: NM_024989
dbSNP: rs147312612
Type: single nucleotide variant
Location: chr2:196841269 (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

Also linked: hereditary spastic paraplegia

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-pro912ser (accessed [today's date]).

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