Is GH1 p.Ser111Pro (c.331T>C) pathogenic?

GH1 p.Ser111Pro (c.331T>C) is classified Uncertain significance in GH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-23). AlphaMissense: likely pathogenic (0.7535); Very rare (popmax 0.005%, nfe); Associated with Inborn genetic diseases.

What condition is associated with GH1 p.Ser111Pro (c.331T>C)?

GH1 p.Ser111Pro (c.331T>C) is associated with Inborn genetic diseases (ClinVar).

How common is GH1 p.Ser111Pro (c.331T>C) in the general population?

GH1 p.Ser111Pro (c.331T>C) is very rare (popmax 0.005%, nfe) (gnomAD).

What do computational predictors say about GH1 p.Ser111Pro (c.331T>C)?

AlphaMissense predicts likely pathogenic (score 0.7535) — an in-silico prediction, not a clinical call.

GH1 p.Ser111Pro

c.331T>C · VCV4858078

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7535 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7535	likely pathogenic · top 9% in GH1
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -10.75	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.1	GERP -0.32, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 1,464 bp · p 0.21 · regional, not allelic
Overall
CADD	23.1	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 0.005% European (non-Finnish) · 59/1,180,030 alleles

Filtering AF 0.00394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00378% 61/1,614,054 alleles · very rare exomes 53/1,461,890 · genomes 8/152,164 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.005%	20,001
African / African-American	0.00267%	37,460

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: GH1
Protein: p.Ser111Pro
Coding: c.331T>C
MANE Select: NM_000515
Type: single nucleotide variant
Location: chr17:63917885 (GRCh38)
Gene constraint: LOEUF 0.838 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.77 · 10 PDB
Residue 111: a turn

Full GH1 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

Similar variants

GH1 p.Asn178= Likely benign ★ same condition
GH1 c.291+1G>A Pathogenic ★★ same type
GH1 c.291+5G>A Pathogenic ★★ same type
GH1 p.Arg209His Pathogenic ★★ ⚠ same type
GH1 p.Glu82Asp Uncertain significance ★★ ⚠ same type
GH1 c.456+19G>T Benign/Likely benign ★★ same type
GH1 c.-38A>C Benign/Likely benign ★★ same type
GH1 c.-4T>G Benign/Likely benign ★★ 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/gh1-p-ser111pro (accessed [today's date]).

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