Is SHOX p.Pro244fs (c.728dup) pathogenic?

SHOX p.Pro244fs (c.728dup) is classified Pathogenic/Likely pathogenic in SHOX (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-05-04). Very rare (popmax 8.75e-05%, nfe); Associated with SHOX-related disorder.

What condition is associated with SHOX p.Pro244fs (c.728dup)?

SHOX p.Pro244fs (c.728dup) is associated with SHOX-related disorder, Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia (ClinVar).

How common is SHOX p.Pro244fs (c.728dup) in the general population?

SHOX p.Pro244fs (c.728dup) is very rare (popmax 8.75e-05%, nfe) (gnomAD).

SHOX p.Pro244fs

c.728dup · rs757845999 · VCV9880

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.75e-05%, nfe)

Conditions

SHOX-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (5 of 5) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.7	GERP 4.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.75e-05% European (non-Finnish) · 1/1,142,332 alleles

Overall 0.000197% 3/1,522,318 alleles · very rare exomes 3/1,370,382 · genomes 0/151,936 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00444%	22,518
European (non-Finnish)grpmax	8.75e-05%	1,142,332

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: SHOX
Protein: p.Pro244fs
Coding: c.728dup
MANE Select: NM_000451
dbSNP: rs757845999
Type: Duplication
Location: chrX:644479 (GRCh38)
Structure: AlphaFold pLDDT 63.90
Residue 244: a UniProt-annotated variant site (in iss; likely pathogenic)

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

Disease context

SHOX-related disorder

Also linked: Leri-Weill dyschondrosteosis Langer mesomelic dysplasia

Similar variants

SHOX p.Pro244Leu Uncertain significance ★ same residue
SHOX c.-19G>A Pathogenic/Likely pathogenic ★★ same condition
SHOX p.Arg168Trp Pathogenic/Likely pathogenic ★★ same condition
SHOX p.Arg173Cys Pathogenic ★★ same condition
SHOX p.Arg173His Pathogenic/Likely pathogenic ★★ same condition
SHOX p.Arg195Ter Pathogenic ★★ same condition
SHOX p.225HPHL[3] Uncertain significance ★★ same condition
SHOX c.277+17T>G Benign ★★ 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/shox-p-pro244fs (accessed [today's date]).

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