Is TPPP p.Ala8Ser (c.22G>T) pathogenic?

TPPP p.Ala8Ser (c.22G>T) is classified Uncertain significance in TPPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely benign (0.074); Absent from gnomAD v4.1.

How common is TPPP p.Ala8Ser (c.22G>T) in the general population?

TPPP p.Ala8Ser (c.22G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TPPP p.Ala8Ser (c.22G>T)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

TPPP p.Ala8Ser

c.22G>T · VCV4598343

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,579,200)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.006	strongly benign-leaning
SaProt	LLR -6.49	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 -2.1	GERP -2.4
Regional constraint	o/e 0.88	unconstrained · MANE · 13 kb · p 0.029 · regional, not allelic
Overall
CADD	6.871	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

No allele count reported in gnomAD v4.1 (AN 1,579,200). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TPPP
Protein: p.Ala8Ser
Coding: c.22G>T
MANE Select: NM_007030
Type: single nucleotide variant
Location: chr5:678039 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI 0.44 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 3 PDB
Residue 8: the 'mediates interaction with limk1' region; the 'disordered' region

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

Similar variants

TPPP p.Arg57= Benign ★★ same type
TPPP p.Gly39Ala Benign ★★ same type
TPPP p.Pro19= Benign/Likely benign ★★ same type
TPPP p.Ala38Val Uncertain significance ★ ⚠ same type
TPPP p.Ala54Thr Uncertain significance ★ ⚠ same type
TPPP p.Arg26Gln Uncertain significance ★ ⚠ same type
TPPP p.Gly39Ser Uncertain significance ★ ⚠ same type
TPPP p.Gly73Ser 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/tppp-p-ala8ser (accessed [today's date]).

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