Is GHSR p.Ile167Phe (c.499A>T) pathogenic?

GHSR p.Ile167Phe (c.499A>T) is classified Uncertain significance in GHSR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-05). AlphaMissense: likely pathogenic (0.7838); Ultra-rare (popmax 0.0433%, amr).

How common is GHSR p.Ile167Phe (c.499A>T) in the general population?

GHSR p.Ile167Phe (c.499A>T) is ultra-rare (popmax 0.0433%, amr) (gnomAD).

What do computational predictors say about GHSR p.Ile167Phe (c.499A>T)?

AlphaMissense predicts likely pathogenic (score 0.7838) — an in-silico prediction, not a clinical call.

GHSR p.Ile167Phe

c.499A>T · rs781009805 · VCV1397925

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7838 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0433%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7838	likely pathogenic
REVEL	0.509	indeterminate
SaProt	LLR -11.76	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.68, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,249 bp · p 0.34 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0433% Admixed American · 26/59,988 alleles

Filtering AF 0.0303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.00161% 26/1,612,566 alleles · ultra-rare exomes 25/1,460,434 · genomes 1/152,132 · 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.Ile167Phe
Coding: c.499A>T
MANE Select: NM_198407
dbSNP: rs781009805
Type: single nucleotide variant
Location: chr3:172447915 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 10 PDB
Residue 167: an α-helix

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

Similar variants

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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
GHSR p.Ile58Met 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-ile167phe (accessed [today's date]).

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