Is GHSR p.Arg237Trp (c.709A>T) pathogenic?

GHSR p.Arg237Trp (c.709A>T) is classified Uncertain significance in GHSR (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-12-03). AlphaMissense: likely benign (0.1939); Rare (popmax 0.264%, mid); Associated with short stature due to GHSR deficiency.

What condition is associated with GHSR p.Arg237Trp (c.709A>T)?

GHSR p.Arg237Trp (c.709A>T) is associated with short stature due to GHSR deficiency (ClinVar).

How common is GHSR p.Arg237Trp (c.709A>T) in the general population?

GHSR p.Arg237Trp (c.709A>T) is rare (popmax 0.264%, 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.

What do computational predictors say about GHSR p.Arg237Trp (c.709A>T)?

AlphaMissense predicts likely benign (score 0.1939) — an in-silico prediction, not a clinical call.

GHSR p.Arg237Trp

c.709A>T · rs199588904 · VCV7634

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1939 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.264%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

short stature due to GHSR deficiency

Computational evidence

Protein change
AlphaMissense	0.1939	likely benign
REVEL	0.548	indeterminate
SaProt	LLR -7.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 0.58, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,249 bp · p 0.34 · regional, not allelic
Overall
CADD	25.3	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 0.264% Middle Eastern · 16/6,062 alleles

Filtering AF 0.165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.135%

Overall 0.0191% 309/1,614,088 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.264%	379
South Asian	0.0494%	2,024
Remaining individualsnot grpmax-eligible	0.0256%	3,906
European (non-Finnish)	0.0192%	5,198
Finnishnot grpmax-eligible	0.00312%	32,008
African / African-American	0.00267%	37,508
Admixed American	0.00167%	60,002

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.Arg237Trp
Coding: c.709A>T
MANE Select: NM_198407
dbSNP: rs199588904
Type: single nucleotide variant
Location: chr3:172447705 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 10 PDB
Residue 237: a UniProt-annotated variant site (in ghdp; results in partial loss of constitutive activity of the receptor; does not affect response to ghrelin; does not affect receptor cell-surface expression); 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.Arg237Lys Uncertain significance ★ ⚠ same residue
GHSR p.Arg141Pro Uncertain significance ★★ ⚠ same condition
GHSR p.Arg206Pro 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
GHSR c.*122C>T 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-arg237trp (accessed [today's date]).

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