Is TULP1 p.Pro2His (c.5C>A) pathogenic?

TULP1 p.Pro2His (c.5C>A) is classified Uncertain significance in TULP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-06). AlphaMissense: likely pathogenic (0.5939); Very rare (popmax 0.004%, afr); Associated with retinitis pigmentosa.

What condition is associated with TULP1 p.Pro2His (c.5C>A)?

TULP1 p.Pro2His (c.5C>A) is associated with retinitis pigmentosa (ClinVar).

How common is TULP1 p.Pro2His (c.5C>A) in the general population?

TULP1 p.Pro2His (c.5C>A) is very rare (popmax 0.004%, afr) (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TULP1 p.Pro2His (c.5C>A)?

AlphaMissense predicts likely pathogenic (score 0.5939) — an in-silico prediction, not a clinical call.

TULP1 p.Pro2His

c.5C>A · rs1174952138 · VCV1297125

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5939 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.5939	likely pathogenic
REVEL	0.454	indeterminate
SaProt	LLR -8.68	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 3,598 bp · p 0.36 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/75,006 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,612,874 alleles · very rare exomes 4/1,460,610 · genomes 0/152,264 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	25,002
Remaining individualsnot grpmax-eligible	0.0016%	62,440

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.Pro2His
Coding: c.5C>A
MANE Select: NM_003322
dbSNP: rs1174952138
Type: single nucleotide variant
Location: chr6:35512854 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB
Residue 2: the 'disordered' region

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

Disease context

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

TULP1 p.Pro2Ser Uncertain significance ★ same residue
TULP1 p.Pro2= Likely benign ★ same residue
TULP1 c.1496-6C>A Pathogenic/Likely pathogenic ★★ same condition
TULP1 p.Asn349Lys Pathogenic/Likely pathogenic ★★ same condition
TULP1 p.Gln163Ter Pathogenic ★★ same condition
TULP1 p.Gln80Ter Pathogenic ★★ same condition
TULP1 p.Phe382Ser Pathogenic ★★ same condition
TULP1 p.Val423Ala Pathogenic/Likely pathogenic ★★ same condition

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-pro2his (accessed [today's date]).

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