Is TIPARP p.Ser656Pro (c.1966T>C) pathogenic?

TIPARP p.Ser656Pro (c.1966T>C) is classified Uncertain significance in TIPARP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely benign (0.1416); Very rare (popmax 0.00801%, amr).

How common is TIPARP p.Ser656Pro (c.1966T>C) in the general population?

TIPARP p.Ser656Pro (c.1966T>C) is very rare (popmax 0.00801%, amr) (gnomAD).

What do computational predictors say about TIPARP p.Ser656Pro (c.1966T>C)?

AlphaMissense predicts likely benign (score 0.1416) — an in-silico prediction, not a clinical call.

TIPARP p.Ser656Pro

c.1966T>C · rs138664121 · VCV3177607

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1416 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1416	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -7.54	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 2.4	phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 397 bp · p 3.6e-11 · regional, not allelic
Overall
CADD	20.5	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 0.00801% Admixed American · 4/49,918 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00115% 17/1,472,664 alleles · very rare exomes 16/1,322,596 · genomes 1/150,068 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00801%	12,480
Remaining individualsnot grpmax-eligible	0.00186%	53,902
African / African-American	0.00143%	70,062
European (non-Finnish)	0.001%	99,834

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.Ser656Pro
Coding: c.1966T>C
MANE Select: NM_015508
dbSNP: rs138664121
Type: single nucleotide variant
Location: chr3:156705123 (GRCh38)
Gene constraint: LOEUF 0.346 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.00
Residue 656: the parp catalytic domain

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

Similar variants

TIPARP p.Ser656Thr 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
TIPARP p.Arg374Trp 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-ser656pro (accessed [today's date]).

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