Is PIGO p.Pro614Arg (c.1841C>G) pathogenic?

PIGO p.Pro614Arg (c.1841C>G) is classified Uncertain significance in PIGO (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: likely benign (0.0789); Very rare (popmax 0.000508%, nfe); Associated with hyperphosphatasia with intellectual disability syndrome 2.

What condition is associated with PIGO p.Pro614Arg (c.1841C>G)?

PIGO p.Pro614Arg (c.1841C>G) is associated with hyperphosphatasia with intellectual disability syndrome 2 (ClinVar).

How common is PIGO p.Pro614Arg (c.1841C>G) in the general population?

PIGO p.Pro614Arg (c.1841C>G) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about PIGO p.Pro614Arg (c.1841C>G)?

AlphaMissense predicts likely benign (score 0.0789) — an in-silico prediction, not a clinical call.

PIGO p.Pro614Arg

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1841C>G · rs749184960 · VCV948886

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0789 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperphosphatasia with intellectual disability syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0789	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -5.87	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 4.6	GERP 1.7, phastCons 0.95
Regional constraint	o/e 0.88	unconstrained · MANE · 6,470 bp · p 2e-05 · regional, not allelic
Overall
CADD	17.61	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000508% European (non-Finnish) · 6/1,180,044 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,614,226 alleles · very rare exomes 7/1,461,886 · genomes 0/152,340 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,046
European (non-Finnish)grpmax	0.000508%	196,674

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: PIGO
Protein: p.Pro614Arg
Coding: c.1841C>G
MANE Select: NM_032634
dbSNP: rs749184960
Type: single nucleotide variant
Location: chr9:35092046 (GRCh38)
Gene constraint: LOEUF 0.89 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.57
Residue 614: a UniProt-annotated variant site (in hpmrs2)

Full PIGO gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyperphosphatasia with intellectual disability syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hyperphosphatasia-intellectual disability syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PIGO p.Pro614Leu Uncertain significance ★★ ⚠ same residue
PIGO p.Pro614Ser Uncertain significance ★ ⚠ same residue
PIGO c.2648-1G>A Likely pathogenic ★★ same condition
PIGO c.3069+2T>C Likely pathogenic ★★ same condition
PIGO c.3069+5G>A Pathogenic/Likely pathogenic ★★ same condition
PIGO p.Arg119Trp Likely pathogenic ★★ ⚠ same condition
PIGO p.Arg122Ter Pathogenic/Likely pathogenic ★★ same condition
PIGO p.Arg376Ter Pathogenic/Likely pathogenic ★★ 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/pigo-p-pro614arg (accessed [today's date]).

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