Is PARP6 p.Ser399Ala (c.1195T>G) pathogenic?

PARP6 p.Ser399Ala (c.1195T>G) is classified Uncertain significance in PARP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1562); Absent from gnomAD v4.1.

How common is PARP6 p.Ser399Ala (c.1195T>G) in the general population?

PARP6 p.Ser399Ala (c.1195T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PARP6 p.Ser399Ala (c.1195T>G)?

AlphaMissense predicts likely benign (score 0.1562) — an in-silico prediction, not a clinical call.

PARP6 p.Ser399Ala

c.1195T>G · VCV4131195

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1562 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1562	likely benign
REVEL	0.235	benign-leaning
SaProt	LLR -9.65	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 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 17 kb · p 2.1e-25 · regional, not allelic
Overall
CADD	23.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PARP6
Protein: p.Ser399Ala
Coding: c.1195T>G
MANE Select: NM_001323532
Type: single nucleotide variant
Location: chr15:72253501 (GRCh38)
Gene constraint: LOEUF 0.451 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.08
Residue 399: the parp catalytic domain

Full PARP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PARP6 c.1491+1G>A Uncertain significance ★ same type
PARP6 p.Ala172Gly Uncertain significance ★ ⚠ same type
PARP6 p.Ala233Glu Uncertain significance ★ ⚠ same type
PARP6 p.Arg207His Uncertain significance ★ ⚠ same type
PARP6 p.Arg248Gln Uncertain significance ★ ⚠ same type
PARP6 p.Arg248Trp Uncertain significance ★ ⚠ same type
PARP6 p.Arg308His Uncertain significance ★ ⚠ same type
PARP6 p.Arg381Gln 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/parp6-p-ser399ala (accessed [today's date]).

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