Is GHSR p.Arg206Pro (c.617G>C) pathogenic?

GHSR p.Arg206Pro (c.617G>C) is classified Uncertain significance in GHSR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-30). AlphaMissense: likely pathogenic (0.7748); Very rare (popmax 0.000169%, nfe); Associated with short stature due to GHSR deficiency.

What condition is associated with GHSR p.Arg206Pro (c.617G>C)?

GHSR p.Arg206Pro (c.617G>C) is associated with short stature due to GHSR deficiency (ClinVar).

How common is GHSR p.Arg206Pro (c.617G>C) in the general population?

GHSR p.Arg206Pro (c.617G>C) is very rare (popmax 0.000169%, nfe) (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.Arg206Pro (c.617G>C)?

AlphaMissense predicts likely pathogenic (score 0.7748) — an in-silico prediction, not a clinical call.

GHSR p.Arg206Pro

c.617G>C · rs777880261 · VCV983070

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7748 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

short stature due to GHSR deficiency

Computational evidence

Protein change
AlphaMissense	0.7748	likely pathogenic
REVEL	0.163	moderately benign-leaning
SaProt	LLR -11.63	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.31	donor loss, 5 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 3.3	GERP 0.12, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,249 bp · p 0.34 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,044 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,032 alleles · very rare exomes 2/1,461,766 · genomes 0/152,266 · joint denominator

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.Arg206Pro
Coding: c.617G>C
MANE Select: NM_198407
dbSNP: rs777880261
Type: single nucleotide variant
Location: chr3:172447797 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 10 PDB
Residue 206: 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.Arg141Pro 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
GHSR c.*122C>T Benign ★★ same condition
GHSR p.Ala48= 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-arg206pro (accessed [today's date]).

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