Is GHSR p.Ala48= (c.144C>T) pathogenic?

GHSR p.Ala48= (c.144C>T) is classified Benign in GHSR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-05-11). Low-frequency (popmax 2.46%, mid); Associated with short stature due to GHSR deficiency.

What condition is associated with GHSR p.Ala48= (c.144C>T)?

GHSR p.Ala48= (c.144C>T) is associated with short stature due to GHSR deficiency (ClinVar).

How common is GHSR p.Ala48= (c.144C>T) in the general population?

GHSR p.Ala48= (c.144C>T) is low-frequency (popmax 2.46%, mid) (gnomAD).

How is Short stature due to GHSR deficiency inherited?

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

GHSR p.Ala48=

c.144C>T · rs2232166 · VCV698146

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.46%, mid)

Conditions

short stature due to GHSR deficiency

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 2.1	GERP -1, phastCons 1
Overall
CADD	11.78	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.46% Middle Eastern · 149/6,062 alleles

Filtering AF 2.14% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.01%

Overall 0.332% 5,361/1,613,176 alleles · low-frequency exomes 4,812/1,460,804 · genomes 549/152,372 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	3.14%	32
Middle Easterngrpmax	2.46%	41
South Asian	1.19%	84
Remaining individualsnot grpmax-eligible	0.738%	136
Admixed American	0.587%	171
African / African-American	0.429%	233
European (non-Finnish)	0.173%	578
East Asian	0.0357%	2,805
Finnishnot grpmax-eligible	0.0142%	7,018

Ashkenazi Jewish 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: GHSR
Protein: p.Ala48=
Coding: c.144C>T
MANE Select: NM_198407
dbSNP: rs2232166
Type: single nucleotide variant
Location: chr3:172448270 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 10 PDB
Residue 48: an α-helix

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

Disease context

short stature due to GHSR deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Short stature due to GHSR deficiency (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

GHSR p.Ala48Asp Uncertain significance ★ ⚠ same residue
GHSR p.Arg141Pro Uncertain significance ★★ ⚠ same condition
GHSR p.Arg206Pro Uncertain significance ★★ ⚠ same condition
GHSR p.Arg237Trp Uncertain significance ★★ ⚠ same condition
GHSR p.Leu42Val Uncertain significance ★★ ⚠ same condition
GHSR p.Lys259Asn Uncertain significance ★★ ⚠ same condition
GHSR p.Ser252Leu Uncertain significance ★★ ⚠ same condition
GHSR c.*114A>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/ghsr-p-ala48 (accessed [today's date]).

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