Is TRPS1 p.Ser616Pro (c.1846T>C) pathogenic?

TRPS1 p.Ser616Pro (c.1846T>C) is classified Uncertain significance in TRPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-27). AlphaMissense: likely benign (0.1648); Very rare (popmax 0.00667%, amr).

How common is TRPS1 p.Ser616Pro (c.1846T>C) in the general population?

TRPS1 p.Ser616Pro (c.1846T>C) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about TRPS1 p.Ser616Pro (c.1846T>C)?

AlphaMissense predicts likely benign (score 0.1648) — an in-silico prediction, not a clinical call.

TRPS1 p.Ser616Pro

c.1846T>C · rs780551240 · VCV2437342

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1648 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1648	likely benign
REVEL	0.276	benign-leaning
SaProt	LLR -6.53	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 9.3	GERP 2.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.11 · regional, not allelic
Overall
CADD	20.8	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 S603P vs ClinVar S616P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,986 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000248% 4/1,614,112 alleles · very rare exomes 4/1,461,814 · genomes 0/152,298 · joint denominator

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.Ser616Pro
Coding: c.1846T>C
MANE Select: NM_014112
dbSNP: rs780551240
Type: single nucleotide variant
Location: chr8:115604123 (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

Similar variants

TRPS1 p.Ser616Phe Uncertain significance ★ ⚠ same residue
TRPS1 p.Ser616Thr Uncertain significance ★ ⚠ same residue
TRPS1 c.2096+2T>G Pathogenic/Likely pathogenic ★★ same type
TRPS1 c.2097-2A>C Pathogenic/Likely pathogenic ★★ same type
TRPS1 p.Ala932Thr Pathogenic/Likely pathogenic ★★ same type
TRPS1 p.Ala932Val Pathogenic ★★ same type
TRPS1 p.Arg257Ter Pathogenic ★★ same type
TRPS1 p.Arg544Ter Pathogenic ★★ same type

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-ser616pro (accessed [today's date]).

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