Is GHSR p.Ser355Arg (c.1065T>A) pathogenic?

GHSR p.Ser355Arg (c.1065T>A) is classified Uncertain significance in GHSR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-10). AlphaMissense: likely benign (0.3005); Very rare (popmax 0.00667%, amr).

How common is GHSR p.Ser355Arg (c.1065T>A) in the general population?

GHSR p.Ser355Arg (c.1065T>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about GHSR p.Ser355Arg (c.1065T>A)?

AlphaMissense predicts likely benign (score 0.3005) — an in-silico prediction, not a clinical call.

GHSR p.Ser355Arg

c.1065T>A · rs138063648 · VCV1981240

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3005 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3005	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -6.55	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 1.6	GERP -0.48, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,249 bp · p 0.34 · regional, not allelic
Overall
CADD	14.98	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 0.00667% Admixed American · 4/59,992 alleles

Filtering AF 0.00538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00498%

Overall 0.00527% 85/1,614,012 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,998
European (non-Finnish)	0.00661%	15,128
Remaining individualsnot grpmax-eligible	0.0032%	31,239
African / African-American	0.00133%	74,920

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.Ser355Arg
Coding: c.1065T>A
MANE Select: NM_198407
dbSNP: rs138063648
Type: single nucleotide variant
Location: chr3:172445197 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 10 PDB

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

Similar variants

GHSR p.Ser355Ile 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-ser355arg (accessed [today's date]).

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