Is TRPS1 p.Ser492Phe (c.1475C>T) pathogenic?

TRPS1 p.Ser492Phe (c.1475C>T) is classified Likely benign in TRPS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-15). AlphaMissense: likely benign (0.1685); Ultra-rare (popmax 0.078%, sas); Associated with trichorhinophalangeal syndrome type I.

What condition is associated with TRPS1 p.Ser492Phe (c.1475C>T)?

TRPS1 p.Ser492Phe (c.1475C>T) is associated with trichorhinophalangeal syndrome type I (ClinVar).

How common is TRPS1 p.Ser492Phe (c.1475C>T) in the general population?

TRPS1 p.Ser492Phe (c.1475C>T) is ultra-rare (popmax 0.078%, sas) (gnomAD).

What do computational predictors say about TRPS1 p.Ser492Phe (c.1475C>T)?

AlphaMissense predicts likely benign (score 0.1685) — an in-silico prediction, not a clinical call.

TRPS1 p.Ser492Phe

c.1475C>T · VCV3462263

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1685 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.078%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

trichorhinophalangeal syndrome type I

Computational evidence

Protein change
AlphaMissense	0.1685	likely benign
REVEL	0.553	indeterminate
SaProt	LLR -8.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.11 · regional, not allelic
Overall
CADD	24.1	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 S479F vs ClinVar S492F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.078% South Asian · 71/91,080 alleles

Filtering AF 0.0633% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.058%

Overall 0.00471% 76/1,614,090 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.078%	1,283
Remaining individualsnot grpmax-eligible	0.0064%	15,627
European (non-Finnish)	8.47e-05%	1,179,986

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.Ser492Phe
Coding: c.1475C>T
MANE Select: NM_014112
Type: single nucleotide variant
Location: chr8:115604494 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.12
Residue 492: the 'disordered' region

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-ser492phe (accessed [today's date]).

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