Is TRPS1 p.Pro617Ser (c.1849C>T) pathogenic?

TRPS1 p.Pro617Ser (c.1849C>T) is classified Conflicting classifications of pathogenicity in TRPS1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-07). AlphaMissense: likely benign (0.095); Ultra-rare (popmax 0.0329%, mid); Associated with trichorhinophalangeal syndrome type I.

What condition is associated with TRPS1 p.Pro617Ser (c.1849C>T)?

TRPS1 p.Pro617Ser (c.1849C>T) is associated with trichorhinophalangeal syndrome type I (ClinVar).

How common is TRPS1 p.Pro617Ser (c.1849C>T) in the general population?

TRPS1 p.Pro617Ser (c.1849C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about TRPS1 p.Pro617Ser (c.1849C>T)?

AlphaMissense predicts likely benign (score 0.095) — an in-silico prediction, not a clinical call.

TRPS1 p.Pro617Ser

c.1849C>T · rs369619683 · VCV596160

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.095 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

trichorhinophalangeal syndrome type I

Computational evidence

Protein change
AlphaMissense	0.095	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -5.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.11 · regional, not allelic
Overall
CADD	16.71	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P604S vs ClinVar P617S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00318%

Overall 0.00514% 83/1,613,992 alleles · ultra-rare exomes 76/1,461,810 · genomes 7/152,182 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.071%	1,409
Middle Easterngrpmax	0.0329%	3,042
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)	0.00449%	22,264
Admixed American	0.00167%	59,970
African / African-American	0.00133%	74,918

Ashkenazi Jewish 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.Pro617Ser
Coding: c.1849C>T
MANE Select: NM_014112
dbSNP: rs369619683
Type: single nucleotide variant
Location: chr8:115604120 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.12

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

Disease context

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

Similar variants

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
TRPS1 p.Arg921Gln 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-pro617ser (accessed [today's date]).

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