Is PROP1 p.Pro210fs (c.629del) pathogenic?

PROP1 p.Pro210fs (c.629del) is classified Likely pathogenic in PROP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-04). Very rare (popmax 0.00177%, nfe); Associated with pituitary hormone deficiency, combined, 2.

What condition is associated with PROP1 p.Pro210fs (c.629del)?

PROP1 p.Pro210fs (c.629del) is associated with pituitary hormone deficiency, combined, 2 (ClinVar).

How common is PROP1 p.Pro210fs (c.629del) in the general population?

PROP1 p.Pro210fs (c.629del) is very rare (popmax 0.00177%, nfe) (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.Pro210fs

c.629del · rs761018422 · VCV1523184

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00177%, nfe)

Conditions

pituitary hormone deficiency, combined, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00177% European (non-Finnish) · 3/169,584 alleles

Filtering AF 0.00047% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000231%

Overall 0.00222% 6/270,460 alleles · very rare exomes 6/243,182 · genomes 0/27,278 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0207%	4,823
Ashkenazi Jewishnot grpmax-eligible	0.0171%	5,832
European (non-Finnish)grpmax	0.00177%	56,528

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro210fs
Coding: c.629del
MANE Select: NM_006261
dbSNP: rs761018422
Type: Deletion
Location: chr5:177992761 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI 0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.74
Residue 210: 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 p.Arg104fs Pathogenic/Likely pathogenic ★★ same condition
PROP1 p.Gly204fs Likely pathogenic ★★ same condition
PROP1 p.Leu131fs Pathogenic/Likely pathogenic ★★ same condition
PROP1 p.Leu22fs Pathogenic ★★ same condition
PROP1 p.Pro32fs Pathogenic/Likely pathogenic ★★ same condition
PROP1 p.Ala186fs Pathogenic ★ same condition
PROP1 p.Gly183fs Likely pathogenic ★ same condition
PROP1 p.Pro210Leu Uncertain significance ★ ⚠ same residue

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-pro210fs (accessed [today's date]).

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