Is PROP1 p.Ser101= (c.303T>C) pathogenic?

PROP1 p.Ser101= (c.303T>C) is classified Likely benign in PROP1 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-01-17). Ultra-rare (popmax 0.0561%, afr); Associated with pituitary hormone deficiency, combined, 2.

What condition is associated with PROP1 p.Ser101= (c.303T>C)?

PROP1 p.Ser101= (c.303T>C) is associated with pituitary hormone deficiency, combined, 2 (ClinVar).

How common is PROP1 p.Ser101= (c.303T>C) in the general population?

PROP1 p.Ser101= (c.303T>C) is ultra-rare (popmax 0.0561%, afr) (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.Ser101=

c.303T>C · rs114584451 · VCV989935

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0561%, afr)

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 -0.17	phastCons 0.001
Overall
CADD	5.695	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0561% African / African-American · 42/74,892 alleles

Filtering AF 0.0426% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0379%

Overall 0.00279% 45/1,613,812 alleles · ultra-rare exomes 26/1,461,874 · genomes 19/151,938 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0561%	1,783
Admixed American	0.00333%	29,996
Remaining individualsnot grpmax-eligible	0.0016%	62,492

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.Ser101=
Coding: c.303T>C
MANE Select: NM_006261
dbSNP: rs114584451
Type: single nucleotide variant
Location: chr5:177994145 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI 0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.74
Residue 101: a DNA-binding 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 p.Ser101Ile Uncertain significance ⚠ 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-ser101 (accessed [today's date]).

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