Is PROP1 p.Ala9= (c.27T>C) pathogenic?

PROP1 p.Ala9= (c.27T>C) is classified Benign in PROP1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). Common (popmax 61.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with pituitary hormone deficiency, combined, 2.

What condition is associated with PROP1 p.Ala9= (c.27T>C)?

PROP1 p.Ala9= (c.27T>C) is associated with pituitary hormone deficiency, combined, 2 (ClinVar).

How is Non-acquired panhypopituitarism inherited?

Typically Autosomal recessive, X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PROP1 p.Ala9=

Q: How common is PROP1 p.Ala9= (c.27T>C) in the general population?

PROP1 p.Ala9= (c.27T>C) is common (popmax 61.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.27T>C · rs1135320 · VCV353017

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 61.6%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

pituitary hormone deficiency, combined, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.83
Overall
CADD	2.617	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 61.6% East Asian · 27,608/44,826 alleles

Filtering AF 61% ClinGen BA1/BS1 input FAF95, joint · FAF99 60.7%

Overall 45.2% 728,800/1,613,148 alleles · common exomes 665,221/1,461,196 · genomes 63,579/151,952 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	61.6%	2
Middle Eastern	58.9%	2
South Asian	57.7%	2
Admixed American	53.9%	2
Ashkenazi Jewishnot grpmax-eligible	52.6%	2
Amishnot grpmax-eligible	50.1%	2
Finnishnot grpmax-eligible	48.4%	2
Remaining individualsnot grpmax-eligible	46%	2
European (non-Finnish)	43.8%	2
African / African-American	28%	4

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: PROP1
Protein: p.Ala9=
Coding: c.27T>C
MANE Select: NM_006261
dbSNP: rs1135320
Type: single nucleotide variant
Location: chr5:177995907 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI 0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.74
Residue 9: the 'disordered' region

Full PROP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pituitary hormone deficiency, combined, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-acquired panhypopituitarism (Orphanet):

Inheritance: Autosomal recessive, X-linked recessive
Onset: All ages

Similar variants

PROP1 c.109+1G>A Pathogenic ★★ same condition
PROP1 c.110-2A>G Likely pathogenic ★★ same condition
PROP1 c.343-1G>A Likely pathogenic ★★ same condition
PROP1 p.Arg112Ter Pathogenic/Likely pathogenic ★★ same condition
PROP1 p.Arg120Cys Pathogenic/Likely pathogenic ★★ same condition
PROP1 p.Arg125Gln Likely pathogenic ★★ same condition
PROP1 p.Arg125Trp Pathogenic ★★ same condition
PROP1 p.Arg16Ter Pathogenic/Likely pathogenic ★★ 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/prop1-p-ala9 (accessed [today's date]).

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