Is TRPS1 p.Pro992= (c.2976G>A) pathogenic?

TRPS1 p.Pro992= (c.2976G>A) is classified Conflicting classifications of pathogenicity in TRPS1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-12). Rare (popmax 0.186%, afr); Associated with Trichorhinophalangeal syndrome, type III.

What condition is associated with TRPS1 p.Pro992= (c.2976G>A)?

TRPS1 p.Pro992= (c.2976G>A) is associated with Trichorhinophalangeal syndrome, type III, trichorhinophalangeal syndrome type I (ClinVar).

How common is TRPS1 p.Pro992= (c.2976G>A) in the general population?

TRPS1 p.Pro992= (c.2976G>A) is rare (popmax 0.186%, afr) (gnomAD).

TRPS1 p.Pro992=

c.2976G>A · rs201030937 · VCV361609

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.186%, afr)

Conditions

Trichorhinophalangeal syndrome, type III

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.209	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -3.7
Overall
CADD	5.609	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.186% African / African-American · 138/74,356 alleles

Filtering AF 0.16% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.151%

Overall 0.0225% 361/1,601,296 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.186%	539
Remaining individualsnot grpmax-eligible	0.0823%	1,215
Middle Eastern	0.0668%	1,496
Admixed American	0.0324%	3,084
European (non-Finnish)	0.0123%	8,151
South Asian	0.00338%	29,624
Finnishnot grpmax-eligible	0.00315%	31,723

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.Pro992=
Coding: c.2976G>A
MANE Select: NM_014112
dbSNP: rs201030937
Type: single nucleotide variant
Location: chr8:115414932 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.12
Residue 992: the 'disordered' region; the 'mediates interaction with rnf4' 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.Pro992Leu Uncertain significance ★★ ⚠ 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
TRPS1 p.Arg696Ter 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-pro992 (accessed [today's date]).

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