Is TULP1 p.Ala221Val (c.662C>T) pathogenic?

TULP1 p.Ala221Val (c.662C>T) is classified Uncertain significance in TULP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-02). AlphaMissense: likely benign (0.0902); Very rare (popmax 0.00549%, sas); Associated with Inborn genetic diseases.

What condition is associated with TULP1 p.Ala221Val (c.662C>T)?

TULP1 p.Ala221Val (c.662C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TULP1 p.Ala221Val (c.662C>T) in the general population?

TULP1 p.Ala221Val (c.662C>T) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about TULP1 p.Ala221Val (c.662C>T)?

AlphaMissense predicts likely benign (score 0.0902) — an in-silico prediction, not a clinical call.

TULP1 p.Ala221Val

c.662C>T · VCV4633962

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0902 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0902	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -6.97	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 1.6	GERP 0.64, phastCons 0.46
Regional constraint	o/e 1.05	unconstrained · MANE · 3,598 bp · p 0.36 · regional, not allelic
Overall
CADD	16.01	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 0.00549% South Asian · 5/91,088 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00031% 5/1,614,120 alleles · very rare exomes 5/1,461,894 · genomes 0/152,226 · 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.Ala221Val
Coding: c.662C>T
MANE Select: NM_003322
Type: single nucleotide variant
Location: chr6:35509690 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB
Residue 221: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TULP1 p.Ala496Val Uncertain significance ★★ ⚠ same condition
TULP1 p.Ala524Thr Uncertain significance ★★ ⚠ same condition
TULP1 p.Ala531Thr Uncertain significance ★★ ⚠ same condition
TULP1 p.Arg159Ser Uncertain significance ★★ ⚠ same condition
TULP1 p.Arg308Gln Uncertain significance ★★ ⚠ same condition
TULP1 p.Arg344Gln Uncertain significance ★★ ⚠ same condition
TULP1 p.Arg416His Uncertain significance ★★ same condition
TULP1 p.Arg438Gln Uncertain significance ★★ ⚠ 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-ala221val (accessed [today's date]).

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