Is GHRL p.Val89Ile (c.265G>A) pathogenic?

GHRL p.Val89Ile (c.265G>A) is classified Uncertain significance in GHRL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-31). AlphaMissense: likely benign (0.0797); Ultra-rare (popmax 0.0318%, sas).

How common is GHRL p.Val89Ile (c.265G>A) in the general population?

GHRL p.Val89Ile (c.265G>A) is ultra-rare (popmax 0.0318%, sas) (gnomAD).

What do computational predictors say about GHRL p.Val89Ile (c.265G>A)?

AlphaMissense predicts likely benign (score 0.0797) — an in-silico prediction, not a clinical call.

GHRL p.Val89Ile

c.265G>A · rs376856625 · VCV2402316

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0797 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0318%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0797	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -7.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.053	GERP -0.32, phastCons 0.13
Regional constraint	o/e 1.36	unconstrained · MANE · 4,302 bp · p 2e-05 · regional, not allelic
Overall
CADD	14.57	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0318% South Asian · 29/91,066 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0196%

Overall 0.00291% 47/1,613,162 alleles · ultra-rare exomes 44/1,460,944 · genomes 3/152,218 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0318%	3,140
Remaining individualsnot grpmax-eligible	0.0048%	20,812
Admixed American	0.00167%	60,014
European (non-Finnish)	0.00119%	84,231

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: GHRL
Protein: p.Val89Ile
Coding: c.265G>A
MANE Select: NM_016362
dbSNP: rs376856625
Type: single nucleotide variant
Location: chr3:10286773 (GRCh38)
Gene constraint: LOEUF 1.822 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.12 · 4 PDB

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

Similar variants

GHRL c.109-36G>A Benign ★★ same type
GHRL c.226-286C>T Benign ★★ same type
GHRL c.226-313A>G Benign ★★ same type
GHRL c.334+138T>G Benign ★★ same type
GHRL p.Gln90Leu Benign ★★ same type
GHRL c.225+2T>G Uncertain significance ★ same type
GHRL c.-771G>A Uncertain significance ★ same type
GHRL c.-789C>T 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/ghrl-p-val89ile (accessed [today's date]).

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