Is GHSR p.Leu91Phe (c.271C>T) pathogenic?

GHSR p.Leu91Phe (c.271C>T) is classified Benign/Likely benign in GHSR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-06-03). AlphaMissense: ambiguous (0.3857); Low-frequency (popmax 1.23%, afr); Associated with short stature due to GHSR deficiency.

What condition is associated with GHSR p.Leu91Phe (c.271C>T)?

GHSR p.Leu91Phe (c.271C>T) is associated with short stature due to GHSR deficiency (ClinVar).

How common is GHSR p.Leu91Phe (c.271C>T) in the general population?

GHSR p.Leu91Phe (c.271C>T) is low-frequency (popmax 1.23%, afr) (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.Leu91Phe (c.271C>T)?

AlphaMissense predicts ambiguous (score 0.3857) — an in-silico prediction, not a clinical call.

GHSR p.Leu91Phe

c.271C>T · rs79053943 · VCV344201

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3857 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.23%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

short stature due to GHSR deficiency

Computational evidence

Protein change
AlphaMissense	0.3857	ambiguous
REVEL	0.246	benign-leaning
SaProt	LLR -8.64	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,249 bp · p 0.34 · regional, not allelic
Overall
CADD	24.8	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 1.23% African / African-American · 924/75,058 alleles

Filtering AF 1.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.14%

Overall 0.068% 1,098/1,614,224 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.23%	81
Admixed American	0.102%	984
Remaining individualsnot grpmax-eligible	0.096%	1,042
South Asian	0.0549%	1,822
European (non-Finnish)	0.000254%	393,349

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.Leu91Phe
Coding: c.271C>T
MANE Select: NM_198407
dbSNP: rs79053943
Type: single nucleotide variant
Location: chr3:172448143 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 10 PDB
Residue 91: 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.Arg206Pro 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

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-leu91phe (accessed [today's date]).

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