Is TULP1 p.Arg508Ser (c.1522C>A) pathogenic?

TULP1 p.Arg508Ser (c.1522C>A) is classified Uncertain significance in TULP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-19). AlphaMissense: likely pathogenic (0.9969); Very rare (popmax 8.47e-05%, nfe).

How common is TULP1 p.Arg508Ser (c.1522C>A) in the general population?

TULP1 p.Arg508Ser (c.1522C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about TULP1 p.Arg508Ser (c.1522C>A)?

AlphaMissense predicts likely pathogenic (score 0.9969) — an in-silico prediction, not a clinical call.

TULP1 p.Arg508Ser

c.1522C>A · rs751036771 · VCV1352501

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9969 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9969	likely pathogenic · top 3% in TULP1
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -14.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 7,948 bp · p 0.64 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 6.2e-05% 1/1,613,956 alleles · very rare exomes 1/1,461,614 · genomes 0/152,342 · joint denominator

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.Arg508Ser
Coding: c.1522C>A
MANE Select: NM_003322
dbSNP: rs751036771
Type: single nucleotide variant
Location: chr6:35498434 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB
Residue 508: a β-strand

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

Similar variants

TULP1 p.Arg508Cys Uncertain significance ★★ ⚠ same residue
TULP1 p.Arg508His Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg508ser (accessed [today's date]).

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