Is PGAP1 p.Tyr626His (c.1876T>C) pathogenic?

PGAP1 p.Tyr626His (c.1876T>C) is classified Conflicting classifications of pathogenicity in PGAP1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-16). AlphaMissense: likely benign (0.3302); Ultra-rare (popmax 0.0421%, nfe); Associated with hereditary spastic paraplegia.

What condition is associated with PGAP1 p.Tyr626His (c.1876T>C)?

PGAP1 p.Tyr626His (c.1876T>C) is associated with hereditary spastic paraplegia, intellectual disability, autosomal recessive 42 (ClinVar).

How common is PGAP1 p.Tyr626His (c.1876T>C) in the general population?

PGAP1 p.Tyr626His (c.1876T>C) is ultra-rare (popmax 0.0421%, nfe) (gnomAD).

What do computational predictors say about PGAP1 p.Tyr626His (c.1876T>C)?

AlphaMissense predicts likely benign (score 0.3302) — an in-silico prediction, not a clinical call.

PGAP1 p.Tyr626His

c.1876T>C · rs150893861 · VCV474989

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3302 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0421%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.3302	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -10.04	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 85 kb · p 0.0064 · regional, not allelic
Overall
CADD	24.7	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 0.0421% European (non-Finnish) · 494/1,174,770 alleles

Filtering AF 0.039% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0377%

Overall 0.0504% 806/1,598,978 alleles · ultra-rare exomes 709/1,446,824 · genomes 97/152,154 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.462%	216
European (non-Finnish)grpmax	0.0421%	2,378
Remaining individualsnot grpmax-eligible	0.0226%	4,421
African / African-American	0.00404%	24,747
Admixed American	0.00177%	56,552

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.Tyr626His
Coding: c.1876T>C
MANE Select: NM_024989
dbSNP: rs150893861
Type: single nucleotide variant
Location: chr2:196848023 (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

hereditary spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability, autosomal recessive 42

Similar variants

PGAP1 p.Tyr626Cys 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-tyr626his (accessed [today's date]).

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