Is TULP1 p.Pro499Ser (c.1495C>T) pathogenic?

TULP1 p.Pro499Ser (c.1495C>T) is classified Uncertain significance in TULP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-16). AlphaMissense: likely benign (0.1146); Rare (popmax 0.144%, afr).

How common is TULP1 p.Pro499Ser (c.1495C>T) in the general population?

TULP1 p.Pro499Ser (c.1495C>T) is rare (popmax 0.144%, afr) (gnomAD).

What do computational predictors say about TULP1 p.Pro499Ser (c.1495C>T)?

AlphaMissense predicts likely benign (score 0.1146) — an in-silico prediction, not a clinical call.

TULP1 p.Pro499Ser

c.1495C>T · rs138772407 · VCV852608

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1146 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.144%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1146	likely benign
REVEL	0.508	indeterminate
SaProt	LLR -9.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP -1.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 7,948 bp · p 0.64 · regional, not allelic
Overall
CADD	20.8	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 0.144% African / African-American · 108/75,016 alleles

Filtering AF 0.122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.114%

Overall 0.00824% 133/1,613,972 alleles · rare exomes 73/1,461,690 · genomes 60/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.144%	695
Remaining individualsnot grpmax-eligible	0.0128%	7,814
Admixed American	0.00833%	12,005
South Asian	0.00659%	15,176
European (non-Finnish)	0.000508%	196,669

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.Pro499Ser
Coding: c.1495C>T
MANE Select: NM_003322
dbSNP: rs138772407
Type: single nucleotide variant
Location: chr6:35499981 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB

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

Similar variants

TULP1 p.Pro499= Likely benign ★ 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-pro499ser (accessed [today's date]).

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