Is TRPS1 p.Ser655= (c.1965G>A) pathogenic?

TRPS1 p.Ser655= (c.1965G>A) is classified Benign/Likely benign in TRPS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-23). Ultra-rare (popmax 0.0357%, eas); Associated with Trichorhinophalangeal syndrome, type III.

What condition is associated with TRPS1 p.Ser655= (c.1965G>A)?

TRPS1 p.Ser655= (c.1965G>A) is associated with Trichorhinophalangeal syndrome, type III, trichorhinophalangeal syndrome type I (ClinVar).

How common is TRPS1 p.Ser655= (c.1965G>A) in the general population?

TRPS1 p.Ser655= (c.1965G>A) is ultra-rare (popmax 0.0357%, eas) (gnomAD).

TRPS1 p.Ser655=

c.1965G>A · rs573826589 · VCV4791780

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, eas)

Conditions

Trichorhinophalangeal syndrome, type III

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 -20	GERP -5.7
Overall
CADD	1.14	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0357% East Asian · 16/44,856 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.0123% 198/1,613,860 alleles · ultra-rare exomes 172/1,461,762 · genomes 26/152,098 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.183%	547
East Asiangrpmax	0.0357%	2,803
Remaining individualsnot grpmax-eligible	0.0176%	5,683
South Asian	0.00549%	18,214
Admixed American	0.005%	19,983
European (non-Finnish)	0.0039%	25,651

Finnish 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: TRPS1
Protein: p.Ser655=
Coding: c.1965G>A
MANE Select: NM_014112
dbSNP: rs573826589
Type: single nucleotide variant
Location: chr8:115604004 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.12
Residue 655: the 'mediates interaction with gli3' 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.Ser655Leu 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
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-ser655 (accessed [today's date]).

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