Is PROP1 p.Ala152= (c.456T>C) pathogenic?

PROP1 p.Ala152= (c.456T>C) is classified Conflicting classifications of pathogenicity in PROP1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-22). Ultra-rare (popmax 0.033%, mid); Associated with pituitary hormone deficiency, combined, 2.

What condition is associated with PROP1 p.Ala152= (c.456T>C)?

PROP1 p.Ala152= (c.456T>C) is associated with pituitary hormone deficiency, combined, 2 (ClinVar).

How common is PROP1 p.Ala152= (c.456T>C) in the general population?

PROP1 p.Ala152= (c.456T>C) is ultra-rare (popmax 0.033%, mid) (gnomAD).

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.Ala152=

c.456T>C · rs758911793 · VCV196433

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

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 -0.033	phastCons 0.004
Overall
CADD	2.329	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,064 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00167% 27/1,613,792 alleles · ultra-rare exomes 26/1,461,782 · genomes 1/152,010 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,032
Admixed American	0.01%	9,991
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
Remaining individualsnot grpmax-eligible	0.0032%	31,239
European (non-Finnish)	0.00136%	73,749

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.Ala152=
Coding: c.456T>C
MANE Select: NM_006261
dbSNP: rs758911793
Type: single nucleotide variant
Location: chr5:177992934 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI 0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.74

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 p.Ala152Thr Likely pathogenic ⚠ same residue
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

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-ala152 (accessed [today's date]).

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