Is GHR p.Pro151Ser (c.451C>T) pathogenic?

GHR p.Pro151Ser (c.451C>T) is classified Uncertain significance in GHR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-16). AlphaMissense: ambiguous (0.4523); Ultra-rare (popmax 0.0123%, nfe); Associated with Inborn genetic diseases.

What condition is associated with GHR p.Pro151Ser (c.451C>T)?

GHR p.Pro151Ser (c.451C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GHR p.Pro151Ser (c.451C>T) in the general population?

GHR p.Pro151Ser (c.451C>T) is ultra-rare (popmax 0.0123%, nfe) (gnomAD).

What do computational predictors say about GHR p.Pro151Ser (c.451C>T)?

AlphaMissense predicts ambiguous (score 0.4523) — an in-silico prediction, not a clinical call.

GHR p.Pro151Ser

c.451C>T · rs201394505 · VCV1416291

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4523 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4523	ambiguous
REVEL	0.909	moderately pathogenic-leaning
SaProt	LLR -8.47	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 154 kb · p 0.32 · regional, not allelic
Overall
CADD	26.9	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 0.0123% European (non-Finnish) · 144/1,173,846 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.01%

Overall 0.0094% 151/1,607,170 alleles · ultra-rare exomes 142/1,454,978 · genomes 9/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0123%	8,152
Remaining individualsnot grpmax-eligible	0.00804%	12,444
Admixed American	0.00334%	29,964

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.Pro151Ser
Coding: c.451C>T
MANE Select: NM_000163
dbSNP: rs201394505
Type: single nucleotide variant
Location: chr5:42699835 (GRCh38)
Gene constraint: LOEUF 0.65 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 59.70 · 11 PDB
Residue 151: the fibronectin type-iii domain; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GHR p.Ala401Gly Uncertain significance ★★ ⚠ same condition
GHR p.Ala421Glu Uncertain significance ★★ ⚠ same condition
GHR p.Arg386His Uncertain significance ★★ ⚠ same condition
GHR p.Arg57His Uncertain significance ★★ ⚠ same condition
GHR p.Asn402Ile Uncertain significance ★★ ⚠ same condition
GHR p.Asp137His Uncertain significance ★★ ⚠ same condition
GHR p.Asp354Val Uncertain significance ★★ ⚠ same condition
GHR p.Asp363Gly 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-pro151ser (accessed [today's date]).

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