Is TULP1 p.Pro175Ala (c.523C>G) pathogenic?

TULP1 p.Pro175Ala (c.523C>G) is classified Uncertain significance in TULP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-18). AlphaMissense: likely benign (0.061); Ultra-rare (popmax 0.099%, mid).

How common is TULP1 p.Pro175Ala (c.523C>G) in the general population?

TULP1 p.Pro175Ala (c.523C>G) is ultra-rare (popmax 0.099%, mid) (gnomAD).

What do computational predictors say about TULP1 p.Pro175Ala (c.523C>G)?

AlphaMissense predicts likely benign (score 0.061) — an in-silico prediction, not a clinical call.

TULP1 p.Pro175Ala

c.523C>G · rs372126191 · VCV842430

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.061 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.099%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.061	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -7.94	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 2.2	GERP -3.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 3,598 bp · p 0.36 · regional, not allelic
Overall
CADD	2.494	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 0.099% Middle Eastern · 6/6,062 alleles

Filtering AF 0.043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0294%

Overall 0.00304% 49/1,613,842 alleles · ultra-rare exomes 49/1,461,688 · genomes 0/152,154 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.099%	1,010
Remaining individualsnot grpmax-eligible	0.0064%	15,626
European (non-Finnish)	0.00314%	31,892
African / African-American	0.00133%	75,008
South Asian	0.0011%	91,070

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.Pro175Ala
Coding: c.523C>G
MANE Select: NM_003322
dbSNP: rs372126191
Type: single nucleotide variant
Location: chr6:35509905 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB
Residue 175: the 'disordered' region

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

Similar variants

TULP1 p.Pro175Thr Uncertain significance ★ ⚠ same residue
TULP1 p.Pro175= Likely benign ★ same residue
TULP1 p.Pro175fs Pathogenic ★ 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

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-pro175ala (accessed [today's date]).

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