Is GHR p.Pro299Ser (c.895C>T) pathogenic?

GHR p.Pro299Ser (c.895C>T) is classified Uncertain significance in GHR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-27). AlphaMissense: likely pathogenic (0.9695); Very rare (popmax 0.000433%, nfe); Associated with short stature due to partial GHR deficiency.

What condition is associated with GHR p.Pro299Ser (c.895C>T)?

GHR p.Pro299Ser (c.895C>T) is associated with short stature due to partial GHR deficiency (ClinVar).

How common is GHR p.Pro299Ser (c.895C>T) in the general population?

GHR p.Pro299Ser (c.895C>T) is very rare (popmax 0.000433%, nfe) (gnomAD).

How is Short stature due to partial GHR deficiency inherited?

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

What do computational predictors say about GHR p.Pro299Ser (c.895C>T)?

AlphaMissense predicts likely pathogenic (score 0.9695) — an in-silico prediction, not a clinical call.

GHR p.Pro299Ser

c.895C>T · rs757458674 · VCV1357046

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9695 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000433%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

short stature due to partial GHR deficiency

Computational evidence

Protein change
AlphaMissense	0.9695	likely pathogenic · top 3% in GHR
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -9.87	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.36	acceptor loss · deltas
Pangolin	Δ0.28	loss · gain 0.27 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 154 kb · p 0.32 · regional, not allelic
Overall
CADD	29.7	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 0.000433% European (non-Finnish) · 5/1,154,926 alleles

Filtering AF 0.000127% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.2e-05%

Overall 0.000315% 5/1,585,802 alleles · very rare exomes 4/1,434,148 · genomes 1/151,654 · 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: GHR
Protein: p.Pro299Ser
Coding: c.895C>T
MANE Select: NM_000163
dbSNP: rs757458674
Type: single nucleotide variant
Location: chr5:42718071 (GRCh38)
Gene constraint: LOEUF 0.65 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 59.70 · 11 PDB
Residue 299: the 'required for jak2 binding' region

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

Disease context

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

For Short stature due to partial GHR deficiency (Orphanet):

Inheritance: Unknown
Onset: Childhood

Similar variants

GHR c.440-1G>A Pathogenic/Likely pathogenic ★★ same condition
GHR p.Arg235Ter Pathogenic ★★ same condition
GHR p.Arg61Ter Pathogenic ★★ same condition
GHR p.Glu198= Pathogenic ★★ same condition
GHR p.Ala421Glu Uncertain significance ★★ ⚠ same condition
GHR p.Arg61Gln Uncertain significance ★★ ⚠ same condition
GHR p.Glu335Lys Uncertain significance ★★ ⚠ same condition
GHR p.Gly166Glu 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/ghr-p-pro299ser (accessed [today's date]).

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