Is TIPRL p.Ser268Arg (c.804T>A) pathogenic?

TIPRL p.Ser268Arg (c.804T>A) is classified Uncertain significance in TIPRL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely benign (0.1183); Very rare (popmax 0.00212%, nfe).

How common is TIPRL p.Ser268Arg (c.804T>A) in the general population?

TIPRL p.Ser268Arg (c.804T>A) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about TIPRL p.Ser268Arg (c.804T>A)?

AlphaMissense predicts likely benign (score 0.1183) — an in-silico prediction, not a clinical call.

TIPRL p.Ser268Arg

c.804T>A · VCV3969027

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1183 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1183	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -7.85	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 -1.4	GERP 1.9
Regional constraint	o/e 0.76	unconstrained · MANE · 21 kb · p 1.6e-05 · regional, not allelic
Overall
CADD	11.85	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 0.00212% European (non-Finnish) · 25/1,179,594 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00161% 26/1,613,264 alleles · very rare exomes 26/1,460,994 · genomes 0/152,270 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00212%	47,184
Remaining individualsnot grpmax-eligible	0.0016%	62,470

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: TIPRL
Protein: p.Ser268Arg
Coding: c.804T>A
MANE Select: NM_152902
Type: single nucleotide variant
Location: chr1:168200031 (GRCh38)
Gene constraint: LOEUF 0.616 · pLI 0.84 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 268: the 'interaction with ppp2ca' region

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

Similar variants

TIPRL p.Ser268Gly Uncertain significance ★ ⚠ same residue
TIPRL p.Arg184Gln Uncertain significance ★ ⚠ same type
TIPRL p.Arg56Gly Uncertain significance ★ ⚠ same type
TIPRL p.Asp264Val Uncertain significance ★ ⚠ same type
TIPRL p.Asp38Asn Uncertain significance ★ ⚠ same type
TIPRL p.Gln146His Uncertain significance ★ ⚠ same type
TIPRL p.Leu125Phe Uncertain significance ★ ⚠ same type
TIPRL p.Leu231Val 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/tiprl-p-ser268arg (accessed [today's date]).

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