Is GHSR p.Trp2Arg (c.4T>C) pathogenic?

GHSR p.Trp2Arg (c.4T>C) is classified Uncertain significance in GHSR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-22). AlphaMissense: ambiguous (0.3674); Very rare (popmax 0.00338%, amr); Associated with Inborn genetic diseases.

What condition is associated with GHSR p.Trp2Arg (c.4T>C)?

GHSR p.Trp2Arg (c.4T>C) is associated with Inborn genetic diseases (ClinVar).

How common is GHSR p.Trp2Arg (c.4T>C) in the general population?

GHSR p.Trp2Arg (c.4T>C) is very rare (popmax 0.00338%, amr) (gnomAD).

What do computational predictors say about GHSR p.Trp2Arg (c.4T>C)?

AlphaMissense predicts ambiguous (score 0.3674) — an in-silico prediction, not a clinical call.

GHSR p.Trp2Arg

c.4T>C · rs767104789 · VCV3099746

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3674 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00338%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3674	ambiguous
REVEL	0.348	indeterminate
SaProt	LLR -6.64	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 0.48, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,249 bp · p 0.34 · regional, not allelic
Overall
CADD	15.58	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 0.00338% Admixed American · 2/59,166 alleles

Filtering AF 0.000561% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00021%

Overall 0.000208% 3/1,439,412 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00338%	29,583
South Asian	0.00111%	89,772

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.Trp2Arg
Coding: c.4T>C
MANE Select: NM_198407
dbSNP: rs767104789
Type: single nucleotide variant
Location: chr3:172448410 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 10 PDB

Full GHSR 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

GHSR p.Trp2Ter Pathogenic same residue
GHSR p.Arg141Pro Uncertain significance ★★ ⚠ same condition
GHSR p.Ile58Met Uncertain significance ★★ ⚠ same condition
GHSR p.Leu274Phe Uncertain significance ★★ ⚠ same condition
GHSR p.Phe220Cys Uncertain significance ★★ ⚠ same condition
GHSR p.Thr229Met Uncertain significance ★★ ⚠ same condition
GHSR p.Thr49Ile Uncertain significance ★★ ⚠ same condition
GHSR p.Thr64Ser 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/ghsr-p-trp2arg (accessed [today's date]).

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