Is TIPARP p.Pro136Ser (c.406C>T) pathogenic?

TIPARP p.Pro136Ser (c.406C>T) is classified Uncertain significance in TIPARP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-23). AlphaMissense: likely benign (0.0705); Ultra-rare (popmax 0.0768%, sas).

How common is TIPARP p.Pro136Ser (c.406C>T) in the general population?

TIPARP p.Pro136Ser (c.406C>T) is ultra-rare (popmax 0.0768%, sas) (gnomAD).

What do computational predictors say about TIPARP p.Pro136Ser (c.406C>T)?

AlphaMissense predicts likely benign (score 0.0705) — an in-silico prediction, not a clinical call.

TIPARP p.Pro136Ser

c.406C>T · rs558453273 · VCV2550517

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0705 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0768%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0705	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -5.54	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 3.2	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 714 bp · p 0.28 · regional, not allelic
Overall
CADD	18.18	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0768% South Asian · 70/91,090 alleles

Filtering AF 0.0624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0571%

Overall 0.00452% 73/1,614,110 alleles · ultra-rare exomes 68/1,461,796 · genomes 5/152,314 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0768%	1,301
Remaining individualsnot grpmax-eligible	0.0032%	31,254
East Asian	0.00223%	44,886

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: TIPARP
Protein: p.Pro136Ser
Coding: c.406C>T
MANE Select: NM_015508
dbSNP: rs558453273
Type: single nucleotide variant
Location: chr3:156678103 (GRCh38)
Gene constraint: LOEUF 0.346 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.00

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

Similar variants

TIPARP p.Pro136Ala Uncertain significance ★ ⚠ same residue
TIPARP p.Pro136Arg Uncertain significance ★ ⚠ same residue
TIPARP p.Arg523= Benign ★★ same type
TIPARP p.Ala124Val Uncertain significance ★ ⚠ same type
TIPARP p.Arg133Leu Uncertain significance ★ ⚠ same type
TIPARP p.Arg272Gly Uncertain significance ★ ⚠ same type
TIPARP p.Arg28Lys Uncertain significance ★ ⚠ same type
TIPARP p.Arg366Gln Uncertain significance ★ ⚠ 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/tiparp-p-pro136ser (accessed [today's date]).

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