Is PGAP1 p.Ala669= (c.2007C>T) pathogenic?

PGAP1 p.Ala669= (c.2007C>T) is classified Benign in PGAP1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-05-01). Low-frequency (popmax 1.31%, nfe); Associated with intellectual disability, autosomal recessive 42.

How common is PGAP1 p.Ala669= (c.2007C>T) in the general population?

PGAP1 p.Ala669= (c.2007C>T) is low-frequency (popmax 1.31%, nfe) (gnomAD).

PGAP1 p.Ala669=

Q: What condition is associated with PGAP1 p.Ala669= (c.2007C>T)?

PGAP1 p.Ala669= (c.2007C>T) is associated with intellectual disability, autosomal recessive 42, hereditary spastic paraplegia (ClinVar).

c.2007C>T · rs149815494 · VCV474991

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.31%, nfe)

Conditions

intellectual disability, autosomal recessive 42

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -1.2, phastCons 1
Overall
CADD	10.67	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.31% European (non-Finnish) · 15,462/1,179,130 alleles

Filtering AF 1.29% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.29%

Overall 1.34% 21,529/1,612,652 alleles · low-frequency exomes 19,565/1,460,644 · genomes 1,964/152,008 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	7.71%	13
Amishnot grpmax-eligible	2.85%	35
European (non-Finnish)grpmax	1.31%	76
Remaining individualsnot grpmax-eligible	0.982%	102
Ashkenazi Jewishnot grpmax-eligible	0.466%	214
Admixed American	0.395%	253
African / African-American	0.179%	559
Middle Eastern	0.033%	3,029
East Asian	0.00223%	44,816
South Asian	0.0022%	45,520

Finnish 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.Ala669=
Coding: c.2007C>T
MANE Select: NM_024989
dbSNP: rs149815494
Type: single nucleotide variant
Location: chr2:196847146 (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.Ala669Thr 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.Arg250His 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-ala669 (accessed [today's date]).

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