Is GNPAT p.Ser249= (c.747T>C) pathogenic?

GNPAT p.Ser249= (c.747T>C) is classified Conflicting classifications of pathogenicity in GNPAT (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-05-01). Ultra-rare (popmax 0.0264%, sas); Associated with rhizomelic chondrodysplasia punctata type 2.

What condition is associated with GNPAT p.Ser249= (c.747T>C)?

GNPAT p.Ser249= (c.747T>C) is associated with rhizomelic chondrodysplasia punctata type 2 (ClinVar).

How common is GNPAT p.Ser249= (c.747T>C) in the general population?

GNPAT p.Ser249= (c.747T>C) is ultra-rare (popmax 0.0264%, sas) (gnomAD).

How is Rhizomelic chondrodysplasia punctata inherited?

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

GNPAT p.Ser249=

c.747T>C · rs202033127 · VCV727943

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0264%, sas)

Conditions

rhizomelic chondrodysplasia punctata type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.49	GERP -1, phastCons 1
Overall
CADD	10.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0264% South Asian · 24/90,876 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0155%

Overall 0.0134% 214/1,602,928 alleles · ultra-rare exomes 193/1,450,688 · genomes 21/152,240 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0264%	3,787
European (non-Finnish)	0.015%	6,647
Remaining individualsnot grpmax-eligible	0.0129%	7,770
Admixed American	0.005%	19,997
Finnishnot grpmax-eligible	0.00312%	32,015
African / African-American	0.00134%	74,702

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: GNPAT
Protein: p.Ser249=
Coding: c.747T>C
MANE Select: NM_014236
dbSNP: rs202033127
Type: single nucleotide variant
Location: chr1:231265762 (GRCh38)
Gene constraint: LOEUF 0.572 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 88.96

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

Disease context

rhizomelic chondrodysplasia punctata type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Rhizomelic chondrodysplasia punctata (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

GNPAT c.569-3T>G Pathogenic ★★ same condition
GNPAT p.Arg163Ter Pathogenic ★★ same condition
GNPAT p.Arg211Cys Likely pathogenic ★★ same condition
GNPAT p.Arg211His Pathogenic ★★ same condition
GNPAT p.Trp386Ter Pathogenic/Likely pathogenic ★★ same condition
GNPAT p.Tyr60Ter Pathogenic/Likely pathogenic ★★ same condition
GNPAT c.924+4C>T Uncertain significance ★★ same condition
GNPAT c.-47C>A 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/gnpat-p-ser249 (accessed [today's date]).

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