Is GHR p.Ser65Pro (c.193T>C) pathogenic?

GHR p.Ser65Pro (c.193T>C) is classified Likely pathogenic in GHR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-30). AlphaMissense: likely pathogenic (0.9859); Very rare (popmax 0.00223%, eas); Associated with growth hormone insensitivity syndrome.

What condition is associated with GHR p.Ser65Pro (c.193T>C)?

GHR p.Ser65Pro (c.193T>C) is associated with growth hormone insensitivity syndrome (ClinVar).

How common is GHR p.Ser65Pro (c.193T>C) in the general population?

GHR p.Ser65Pro (c.193T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about GHR p.Ser65Pro (c.193T>C)?

AlphaMissense predicts likely pathogenic (score 0.9859) — an in-silico prediction, not a clinical call.

GHR p.Ser65Pro

c.193T>C · VCV3339481

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9859 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

growth hormone insensitivity syndrome

Computational evidence

Protein change
AlphaMissense	0.9859	likely pathogenic ✓ concordant with ClinVar · top 1% in GHR
REVEL	0.715	pathogenic-leaning
SaProt	LLR -14.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 154 kb · p 0.32 · 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 0.00223% East Asian · 1/44,868 alleles

Overall 6.2e-05% 1/1,613,396 alleles · very rare exomes 1/1,461,120 · genomes 0/152,276 · 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.Ser65Pro
Coding: c.193T>C
MANE Select: NM_000163
Type: single nucleotide variant
Location: chr5:42688946 (GRCh38)
Gene constraint: LOEUF 0.65 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 59.70 · 11 PDB
Residue 65: a β-strand

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

Disease context

growth hormone insensitivity syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GHR p.Ser65fs Pathogenic ★★ same residue
GHR p.Ser65= Conflicting classifications of pathogenicity ★ same residue
GHR c.618+792A>G Pathogenic/Likely pathogenic ★★ same condition
GHR p.Cys56Ter Pathogenic ★★ same condition
GHR p.Pro149Gln Likely pathogenic ★ same condition
GHR p.Trp34Ter Pathogenic ★ same condition
GHR p.Glu62Lys Conflicting classifications of pathogenicity ★ ⚠ same condition
GHR c.266+83G>T Pathogenic/Likely pathogenic ★★ same type

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-ser65pro (accessed [today's date]).

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