Is GHSR p.Val216Ala (c.647T>C) pathogenic?

GHSR p.Val216Ala (c.647T>C) is classified Uncertain significance in GHSR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-09). AlphaMissense: likely benign (0.31); Ultra-rare (popmax 0.066%, mid); Associated with Inborn genetic diseases.

What condition is associated with GHSR p.Val216Ala (c.647T>C)?

GHSR p.Val216Ala (c.647T>C) is associated with Inborn genetic diseases (ClinVar).

How common is GHSR p.Val216Ala (c.647T>C) in the general population?

GHSR p.Val216Ala (c.647T>C) is ultra-rare (popmax 0.066%, mid) (gnomAD).

What do computational predictors say about GHSR p.Val216Ala (c.647T>C)?

AlphaMissense predicts likely benign (score 0.31) — an in-silico prediction, not a clinical call.

GHSR p.Val216Ala

c.647T>C · rs200619653 · VCV2381730

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.31 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.31	likely benign
REVEL	0.361	indeterminate
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.30	donor loss, 6 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 9.4	GERP 0.76, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,249 bp · p 0.34 · regional, not allelic
Overall
CADD	26.6	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 0.066% Middle Eastern · 4/6,062 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.0031% 50/1,614,092 alleles · ultra-rare exomes 41/1,461,844 · genomes 9/152,248 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,516
African / African-American	0.0133%	7,502
Remaining individualsnot grpmax-eligible	0.0112%	8,930
Admixed American	0.00666%	15,004
European (non-Finnish)	0.00212%	47,201

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.Val216Ala
Coding: c.647T>C
MANE Select: NM_198407
dbSNP: rs200619653
Type: single nucleotide variant
Location: chr3:172447767 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 10 PDB
Residue 216: an α-helix

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

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GHSR p.Ala144Val 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-val216ala (accessed [today's date]).

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