Is GHSR p.Ala48Asp (c.143C>A) pathogenic?

GHSR p.Ala48Asp (c.143C>A) is classified Uncertain significance in GHSR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-19). AlphaMissense: likely pathogenic (0.9411); Very rare (popmax 0.00017%, nfe).

How common is GHSR p.Ala48Asp (c.143C>A) in the general population?

GHSR p.Ala48Asp (c.143C>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about GHSR p.Ala48Asp (c.143C>A)?

AlphaMissense predicts likely pathogenic (score 0.9411) — an in-silico prediction, not a clinical call.

GHSR p.Ala48Asp

c.143C>A · VCV4686497

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9411 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9411	likely pathogenic
REVEL	0.246	benign-leaning
SaProt	LLR -14.47	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,249 bp · p 0.34 · regional, not allelic
Overall
CADD	28.8	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 0.00017% European (non-Finnish) · 2/1,179,930 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,612,968 alleles · very rare

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.Ala48Asp
Coding: c.143C>A
MANE Select: NM_198407
Type: single nucleotide variant
Location: chr3:172448271 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 10 PDB
Residue 48: an α-helix

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

Similar variants

GHSR p.Ala48= Benign ★★ same residue
GHSR p.Arg141Leu Uncertain significance ★★ ⚠ same type
GHSR p.Arg141Pro Uncertain significance ★★ ⚠ same type
GHSR p.Arg206Pro Uncertain significance ★★ ⚠ same type
GHSR p.Arg237Trp Uncertain significance ★★ ⚠ same type
GHSR p.Arg283Ter Uncertain significance ★★ same type
GHSR p.Glu73Asp Uncertain significance ★★ ⚠ same type
GHSR p.Glu9Lys Uncertain significance ★★ ⚠ 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/ghsr-p-ala48asp (accessed [today's date]).

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