Is TRPS1 p.Ser103Arg (c.309C>A) pathogenic?

TRPS1 p.Ser103Arg (c.309C>A) is classified Conflicting classifications of pathogenicity in TRPS1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-31). AlphaMissense: likely pathogenic (0.6123); Ultra-rare (popmax 0.024%, afr); Associated with Inborn genetic diseases.

What condition is associated with TRPS1 p.Ser103Arg (c.309C>A)?

TRPS1 p.Ser103Arg (c.309C>A) is associated with Inborn genetic diseases, trichorhinophalangeal syndrome type I (ClinVar).

How common is TRPS1 p.Ser103Arg (c.309C>A) in the general population?

TRPS1 p.Ser103Arg (c.309C>A) is ultra-rare (popmax 0.024%, afr) (gnomAD).

What do computational predictors say about TRPS1 p.Ser103Arg (c.309C>A)?

AlphaMissense predicts likely pathogenic (score 0.6123) — an in-silico prediction, not a clinical call.

TRPS1 p.Ser103Arg

c.309C>A · VCV4191895

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6123 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6123	likely pathogenic
REVEL	0.528	indeterminate
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.11 · regional, not allelic
Overall
CADD	26.0	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 S90R vs ClinVar S103R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.024% African / African-American · 18/74,910 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00118% 19/1,614,038 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.024%	4,162
European (non-Finnish)	8.47e-05%	1,180,032

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.Ser103Arg
Coding: c.309C>A
MANE Select: NM_014112
Type: single nucleotide variant
Location: chr8:115619789 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.12
Residue 103: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: trichorhinophalangeal syndrome type I

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-ser103arg (accessed [today's date]).

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