Is TULP1 p.Arg420Ser (c.1258C>A) pathogenic?

TULP1 p.Arg420Ser (c.1258C>A) is classified Pathogenic in TULP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.9437); Very rare (popmax 0.00227%, eas); Associated with TULP1-related disorder.

What condition is associated with TULP1 p.Arg420Ser (c.1258C>A)?

TULP1 p.Arg420Ser (c.1258C>A) is associated with TULP1-related disorder, Leber congenital amaurosis (ClinVar).

How common is TULP1 p.Arg420Ser (c.1258C>A) in the general population?

TULP1 p.Arg420Ser (c.1258C>A) is very rare (popmax 0.00227%, eas) (gnomAD).

What do computational predictors say about TULP1 p.Arg420Ser (c.1258C>A)?

AlphaMissense predicts likely pathogenic (score 0.9437) — an in-silico prediction, not a clinical call.

TULP1 p.Arg420Ser

c.1258C>A · rs551519696 · VCV1366826

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9437 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00227%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TULP1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9437	likely pathogenic ✓ concordant with ClinVar
REVEL	0.851	moderately pathogenic-leaning
SaProt	LLR -10.95	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 7.5	GERP -0.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 7,948 bp · p 0.64 · regional, not allelic
Overall
CADD	28.6	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 0.00227% East Asian · 1/44,128 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00124%

Overall 0.00175% 28/1,599,194 alleles · very rare exomes 26/1,446,972 · genomes 2/152,222 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00227%	44,128
South Asian	0.00227%	44,145
European (non-Finnish)	0.00213%	46,928

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.Arg420Ser
Coding: c.1258C>A
MANE Select: NM_003322
dbSNP: rs551519696
Type: single nucleotide variant
Location: chr6:35503624 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB
Residue 420: a UniProt-annotated variant site (in rp14; no effect on rpe phagocytosis)

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

Disease context

TULP1-related disorder

Also linked: Leber congenital amaurosis

Similar variants

TULP1 p.Arg420His Uncertain significance ★★ ⚠ same residue
TULP1 p.Arg420Cys Likely pathogenic ★ same residue
TULP1 p.Arg420Pro Pathogenic ★ same residue
TULP1 p.Arg420Leu Uncertain significance ★ ⚠ same residue
TULP1 c.1112+1G>A Likely pathogenic ★★ same condition
TULP1 c.1495+1G>A Pathogenic/Likely pathogenic ★★ same condition
TULP1 c.1496-6C>A Pathogenic/Likely pathogenic ★★ same condition
TULP1 c.718+2T>C 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-arg420ser (accessed [today's date]).

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