Is TRPS1 p.Pro141= (c.423G>T) pathogenic?

TRPS1 p.Pro141= (c.423G>T) is classified Benign in TRPS1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). Common (popmax 46.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Trichorhinophalangeal syndrome, type III.

What condition is associated with TRPS1 p.Pro141= (c.423G>T)?

TRPS1 p.Pro141= (c.423G>T) is associated with Trichorhinophalangeal syndrome, type III, trichorhinophalangeal syndrome type I (ClinVar).

TRPS1 p.Pro141=

Q: How common is TRPS1 p.Pro141= (c.423G>T) in the general population?

TRPS1 p.Pro141= (c.423G>T) is common (popmax 46.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.423G>T · rs7823278 · VCV260333

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 46.8%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Trichorhinophalangeal syndrome, type III

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.2	GERP 1.5, phastCons 1
Overall
CADD	10.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 46.8% African / African-American · 35,068/74,930 alleles

Filtering AF 46.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 46.2%

Overall 2.82% 45,534/1,614,012 alleles · common exomes 24,938/1,461,880 · genomes 20,596/152,132 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	46.8%	2
South Asian	4.2%	24
Remaining individualsnot grpmax-eligible	3.88%	26
Admixed American	3.8%	26
Middle Eastern	3.35%	30
Ashkenazi Jewishnot grpmax-eligible	0.513%	195
European (non-Finnish)	0.134%	749
East Asian	0.0134%	7,477
Finnishnot grpmax-eligible	0.00312%	32,016

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: TRPS1
Protein: p.Pro141=
Coding: c.423G>T
MANE Select: NM_014112
dbSNP: rs7823278
Type: single nucleotide variant
Location: chr8:115619675 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.12
Residue 141: the 'disordered' region

Full TRPS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Trichorhinophalangeal syndrome, type III — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: trichorhinophalangeal syndrome type I

Similar variants

TRPS1 p.Pro141Gln Uncertain significance ★ ⚠ same residue
TRPS1 p.Pro141Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TRPS1 c.2097-2A>C Pathogenic/Likely pathogenic ★★ same condition
TRPS1 p.Ala932Thr Pathogenic/Likely pathogenic ★★ same condition
TRPS1 p.Ala932Val Pathogenic ★★ same condition
TRPS1 p.Arg257Ter Pathogenic ★★ same condition
TRPS1 p.Arg544Ter Pathogenic ★★ same condition
TRPS1 p.Arg624Ter 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/trps1-p-pro141 (accessed [today's date]).

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