Is TULP1 p.Pro174Arg (c.521C>G) pathogenic?

TULP1 p.Pro174Arg (c.521C>G) is classified Uncertain significance in TULP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-13). AlphaMissense: likely benign (0.0793); Ultra-rare (popmax 0.0321%, afr).

How common is TULP1 p.Pro174Arg (c.521C>G) in the general population?

TULP1 p.Pro174Arg (c.521C>G) is ultra-rare (popmax 0.0321%, afr) (gnomAD).

What do computational predictors say about TULP1 p.Pro174Arg (c.521C>G)?

AlphaMissense predicts likely benign (score 0.0793) — an in-silico prediction, not a clinical call.

TULP1 p.Pro174Arg

c.521C>G · rs375213186 · VCV1310266

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0793 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0321%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0793	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -8.43	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 1.2	GERP -0.68, phastCons 0.69
Regional constraint	o/e 1.05	unconstrained · MANE · 3,598 bp · p 0.36 · regional, not allelic
Overall
CADD	14.02	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 0.0321% African / African-American · 24/74,882 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.00229% 37/1,613,738 alleles · ultra-rare exomes 24/1,461,678 · genomes 13/152,060 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0321%	3,120
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0096%	10,414
South Asian	0.00659%	15,179

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: TULP1
Protein: p.Pro174Arg
Coding: c.521C>G
MANE Select: NM_003322
dbSNP: rs375213186
Type: single nucleotide variant
Location: chr6:35509907 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB
Residue 174: the 'disordered' region

Full TULP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TULP1 p.Pro174Ser Uncertain significance ★★ ⚠ same residue
TULP1 c.1112+1G>A Likely pathogenic ★★ same type
TULP1 c.1495+1G>A Pathogenic/Likely pathogenic ★★ same type
TULP1 c.1496-6C>A Pathogenic/Likely pathogenic ★★ same type
TULP1 c.718+2T>C Pathogenic ★★ same type
TULP1 c.99+1G>A Pathogenic/Likely pathogenic ★★ same type
TULP1 c.999+5G>C Pathogenic/Likely pathogenic ★★ same type
TULP1 p.Arg311Gln Pathogenic/Likely pathogenic ★★ 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/tulp1-p-pro174arg (accessed [today's date]).

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