Is PROP1 p.Ala142Val (c.425C>T) pathogenic?

PROP1 p.Ala142Val (c.425C>T) is classified Conflicting classifications of pathogenicity in PROP1 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0989); Rare (popmax 0.298%, nfe); Associated with pituitary hormone deficiency, combined, 2.

What condition is associated with PROP1 p.Ala142Val (c.425C>T)?

PROP1 p.Ala142Val (c.425C>T) is associated with pituitary hormone deficiency, combined, 2, amenorrhea (ClinVar).

How common is PROP1 p.Ala142Val (c.425C>T) in the general population?

PROP1 p.Ala142Val (c.425C>T) is rare (popmax 0.298%, 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.

What do computational predictors say about PROP1 p.Ala142Val (c.425C>T)?

AlphaMissense predicts likely benign (score 0.0989) — an in-silico prediction, not a clinical call.

PROP1 p.Ala142Val

c.425C>T · rs143790367 · VCV196432

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0989 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.298%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pituitary hormone deficiency, combined, 2

Computational evidence

Protein change
AlphaMissense	0.0989	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -8.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 3,221 bp · p 0.32 · regional, not allelic
Overall
CADD	11.12	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

Grpmax group 0.298% European (non-Finnish) · 3,517/1,179,998 alleles

Filtering AF 0.29% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.286%

Overall 0.255% 4,116/1,614,046 alleles · rare exomes 3,826/1,461,822 · genomes 290/152,224 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.726%	138
European (non-Finnish)grpmax	0.298%	336
Middle Eastern	0.298%	336
Remaining individualsnot grpmax-eligible	0.224%	446
Admixed American	0.135%	741
Finnishnot grpmax-eligible	0.127%	790
African / African-American	0.0467%	2,143
South Asian	0.0318%	3,140

Ashkenazi Jewish 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.Ala142Val
Coding: c.425C>T
MANE Select: NM_006261
dbSNP: rs143790367
Type: single nucleotide variant
Location: chr5:177992965 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI 0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.74
Residue 142: a UniProt-annotated variant site (in)

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

Also linked: amenorrhea

For Non-acquired panhypopituitarism (Orphanet):

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

Similar variants

PROP1 p.Ala142Thr Benign/Likely benign ★★ same residue
PROP1 p.Ala142= 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

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-ala142val (accessed [today's date]).

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