Is GHSR p.Ala333= (c.999A>G) pathogenic?

GHSR p.Ala333= (c.999A>G) is classified Likely benign in GHSR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). Very rare (popmax 0.004%, afr).

How common is GHSR p.Ala333= (c.999A>G) in the general population?

GHSR p.Ala333= (c.999A>G) is very rare (popmax 0.004%, afr) (gnomAD).

GHSR p.Ala333=

c.999A>G · VCV3609453

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.9
Overall
CADD	0.094	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,908 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,614,042 alleles · very rare exomes 1/1,461,884 · genomes 2/152,158 · 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: GHSR
Protein: p.Ala333=
Coding: c.999A>G
MANE Select: NM_198407
Type: single nucleotide variant
Location: chr3:172445263 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 10 PDB
Residue 333: an α-helix

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

Similar variants

GHSR p.Ala333Val Uncertain significance ★ ⚠ 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-ala333 (accessed [today's date]).

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