Is PROP1 p.Ala141= (c.423C>T) pathogenic?

PROP1 p.Ala141= (c.423C>T) is classified Conflicting classifications of pathogenicity in PROP1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-12). Ultra-rare (popmax 0.0133%, amr).

How common is PROP1 p.Ala141= (c.423C>T) in the general population?

PROP1 p.Ala141= (c.423C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

PROP1 p.Ala141=

c.423C>T · rs200977367 · VCV286282

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

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 0.56	phastCons 0.075
Overall
CADD	5.553	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/59,980 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00297% 48/1,613,908 alleles · ultra-rare exomes 37/1,461,794 · genomes 11/152,114 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,497
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
Remaining individualsnot grpmax-eligible	0.0032%	31,238
European (non-Finnish)	0.00297%	33,715
African / African-American	0.00267%	37,451

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.Ala141=
Coding: c.423C>T
MANE Select: NM_006261
dbSNP: rs200977367
Type: single nucleotide variant
Location: chr5:177992967 (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

Similar variants

PROP1 c.109+1G>A Pathogenic ★★ same type
PROP1 c.110-2A>G Likely pathogenic ★★ same type
PROP1 c.343-1G>A Likely pathogenic ★★ same type
PROP1 p.Arg112Ter Pathogenic/Likely pathogenic ★★ same type
PROP1 p.Arg120Cys Pathogenic/Likely pathogenic ★★ same type
PROP1 p.Arg125Gln Likely pathogenic ★★ same type
PROP1 p.Arg125Trp Pathogenic ★★ same type
PROP1 p.Arg16Ter Pathogenic/Likely pathogenic ★★ same type

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-ala141 (accessed [today's date]).

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