Is PROP1 p.Pro209Arg (c.626C>G) pathogenic?

PROP1 p.Pro209Arg (c.626C>G) is classified Likely pathogenic in PROP1 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely benign (0.1362); Absent from gnomAD v4.1; Associated with pituitary hormone deficiency, combined, 2.

What condition is associated with PROP1 p.Pro209Arg (c.626C>G)?

PROP1 p.Pro209Arg (c.626C>G) is associated with pituitary hormone deficiency, combined, 2 (ClinVar).

How common is PROP1 p.Pro209Arg (c.626C>G) in the general population?

PROP1 p.Pro209Arg (c.626C>G) is absent from gnomAD v4.1 (gnomAD).

How is Non-acquired panhypopituitarism inherited?

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

What do computational predictors say about PROP1 p.Pro209Arg (c.626C>G)?

AlphaMissense predicts likely benign (score 0.1362) — an in-silico prediction, not a clinical call.

PROP1 p.Pro209Arg

c.626C>G · VCV4073493

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1362 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

pituitary hormone deficiency, combined, 2

Computational evidence

Protein change
AlphaMissense	0.1362	likely benign ⚠ discordant with ClinVar
REVEL	0.303	indeterminate
SaProt	LLR -12.32	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 3,221 bp · p 0.32 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PROP1
Protein: p.Pro209Arg
Coding: c.626C>G
MANE Select: NM_006261
Type: single nucleotide variant
Location: chr5:177992764 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI 0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.74
Residue 209: 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.Pro209= Likely benign ★ 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-pro209arg (accessed [today's date]).

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