Is TIPRL p.Val174Ile (c.520G>A) pathogenic?

TIPRL p.Val174Ile (c.520G>A) is classified Uncertain significance in TIPRL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-11). AlphaMissense: likely benign (0.2481); Rare (popmax 0.257%, eas).

How common is TIPRL p.Val174Ile (c.520G>A) in the general population?

TIPRL p.Val174Ile (c.520G>A) is rare (popmax 0.257%, eas) (gnomAD).

What do computational predictors say about TIPRL p.Val174Ile (c.520G>A)?

AlphaMissense predicts likely benign (score 0.2481) — an in-silico prediction, not a clinical call.

TIPRL p.Val174Ile

c.520G>A · rs764532151 · VCV2289022

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2481 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.257%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2481	likely benign
REVEL	0.287	benign-leaning
SaProt	LLR -9.27	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 12	GERP 4.2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 21 kb · p 1.6e-05 · regional, not allelic
Overall
CADD	23.1	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 0.257% East Asian · 111/43,218 alleles

Filtering AF 0.218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.203%

Overall 0.00726% 113/1,555,474 alleles · rare exomes 109/1,409,660 · genomes 4/145,814 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.257%	389
Remaining individualsnot grpmax-eligible	0.00167%	60,060
European (non-Finnish)	8.69e-05%	1,150,948

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.Val174Ile
Coding: c.520G>A
MANE Select: NM_152902
dbSNP: rs764532151
Type: single nucleotide variant
Location: chr1:168196550 (GRCh38)
Gene constraint: LOEUF 0.616 · pLI 0.84 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 174: the 'interaction with ppp2ca' region; a β-strand

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

Similar variants

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
TIPRL p.Lys148Asn 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-val174ile (accessed [today's date]).

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