Is PGAP1 p.Gln585Glu (c.1753C>G) pathogenic?

PGAP1 p.Gln585Glu (c.1753C>G) is classified Benign/Likely benign in PGAP1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.0799); Rare (popmax 0.667%, nfe); Associated with intellectual disability, autosomal recessive 42.

What condition is associated with PGAP1 p.Gln585Glu (c.1753C>G)?

PGAP1 p.Gln585Glu (c.1753C>G) is associated with intellectual disability, autosomal recessive 42, hereditary spastic paraplegia (ClinVar).

How common is PGAP1 p.Gln585Glu (c.1753C>G) in the general population?

PGAP1 p.Gln585Glu (c.1753C>G) is rare (popmax 0.667%, nfe) (gnomAD).

What do computational predictors say about PGAP1 p.Gln585Glu (c.1753C>G)?

AlphaMissense predicts likely benign (score 0.0799) — an in-silico prediction, not a clinical call.

PGAP1 p.Gln585Glu

c.1753C>G · rs62185645 · VCV436291

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0799 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.667%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal recessive 42

Computational evidence

Protein change
AlphaMissense	0.0799	likely benign
REVEL	0.145	moderately benign-leaning
SaProt	LLR -3.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 85 kb · p 0.0064 · regional, not allelic
Overall
CADD	21.5	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 0.667% European (non-Finnish) · 7,828/1,174,138 alleles

Filtering AF 0.654% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.649%

Overall 0.54% 8,679/1,606,892 alleles · rare exomes 8,076/1,454,726 · genomes 603/152,166 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.667%	150
Remaining individualsnot grpmax-eligible	0.57%	175
Finnishnot grpmax-eligible	0.46%	217
Admixed American	0.192%	521
African / African-American	0.11%	913
Middle Eastern	0.0331%	3,021
Ashkenazi Jewishnot grpmax-eligible	0.00677%	14,774
South Asian	0.0022%	45,420

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.Gln585Glu
Coding: c.1753C>G
MANE Select: NM_024989
dbSNP: rs62185645
Type: single nucleotide variant
Location: chr2:196870955 (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.Gln585= Likely benign ★★ 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-gln585glu (accessed [today's date]).

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