Is TRPS1 p.Lys754Arg (c.2261A>G) pathogenic?

TRPS1 p.Lys754Arg (c.2261A>G) is classified Uncertain significance in TRPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-29). AlphaMissense: likely benign (0.0972); Very rare (popmax 6.84e-05%); Associated with Inborn genetic diseases.

What condition is associated with TRPS1 p.Lys754Arg (c.2261A>G)?

TRPS1 p.Lys754Arg (c.2261A>G) is associated with Inborn genetic diseases (ClinVar).

How common is TRPS1 p.Lys754Arg (c.2261A>G) in the general population?

TRPS1 p.Lys754Arg (c.2261A>G) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about TRPS1 p.Lys754Arg (c.2261A>G)?

AlphaMissense predicts likely benign (score 0.0972) — an in-silico prediction, not a clinical call.

TRPS1 p.Lys754Arg

c.2261A>G · VCV3462271

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0972	likely benign
REVEL	0.575	indeterminate
SaProt	LLR -7.28	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 4.2	GERP 2.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.11 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM K741R vs ClinVar K754R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,882 alleles · very rare

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.Lys754Arg
Coding: c.2261A>G
MANE Select: NM_014112
Type: single nucleotide variant
Location: chr8:115587440 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.12
Residue 741 UniProt numbering: the 'mediates interaction with gli3' 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

Similar variants

TRPS1 p.Arg696Ter Pathogenic ★★ same condition
TRPS1 p.Ala196Val Uncertain significance ★★ ⚠ same condition
TRPS1 p.Ala848Thr Uncertain significance ★★ ⚠ same condition
TRPS1 p.Arg1125Gln Uncertain significance ★★ ⚠ same condition
TRPS1 p.Asn738Ser Uncertain significance ★★ ⚠ same condition
TRPS1 p.Cys704Ser Uncertain significance ★★ ⚠ same condition
TRPS1 p.Gln1020His Uncertain significance ★★ ⚠ same condition
TRPS1 p.Gly1063Glu Uncertain significance ★★ 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-lys754arg (accessed [today's date]).

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