Is TRPS1 p.Ser667= (c.2001G>A) pathogenic?

TRPS1 p.Ser667= (c.2001G>A) is classified Likely benign in TRPS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-10). Ultra-rare (popmax 0.0165%, mid); Associated with Trichorhinophalangeal syndrome, type III.

What condition is associated with TRPS1 p.Ser667= (c.2001G>A)?

TRPS1 p.Ser667= (c.2001G>A) is associated with Trichorhinophalangeal syndrome, type III, trichorhinophalangeal syndrome type I (ClinVar).

How common is TRPS1 p.Ser667= (c.2001G>A) in the general population?

TRPS1 p.Ser667= (c.2001G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

TRPS1 p.Ser667=

c.2001G>A · rs766238512 · VCV1127869

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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 -8.1	GERP -5.7
Overall
CADD	0.284	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000929% 15/1,613,972 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
South Asian	0.00769%	13,012
European (non-Finnish)	0.000593%	168,568

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.Ser667=
Coding: c.2001G>A
MANE Select: NM_014112
dbSNP: rs766238512
Type: single nucleotide variant
Location: chr8:115603968 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.12
Residue 667: 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.Ser667Leu Likely benign ★ 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-ser667 (accessed [today's date]).

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