Is LARGE1 p.Val697Leu (c.2089G>T) pathogenic?

LARGE1 p.Val697Leu (c.2089G>T) is classified Pathogenic in LARGE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-30). AlphaMissense: likely pathogenic (0.9427); Very rare (popmax 8.47e-05%, nfe); Associated with retinitis pigmentosa.

What condition is associated with LARGE1 p.Val697Leu (c.2089G>T)?

LARGE1 p.Val697Leu (c.2089G>T) is associated with retinitis pigmentosa (ClinVar).

How common is LARGE1 p.Val697Leu (c.2089G>T) in the general population?

LARGE1 p.Val697Leu (c.2089G>T) is very rare (popmax 8.47e-05%, nfe) (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 LARGE1 p.Val697Leu (c.2089G>T)?

AlphaMissense predicts likely pathogenic (score 0.9427) — an in-silico prediction, not a clinical call.

LARGE1 p.Val697Leu

c.2089G>T · rs1602190224 · VCV684425

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9427 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.9427	likely pathogenic ✓ concordant with ClinVar
REVEL	0.441	indeterminate
SaProt	LLR -9.06	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 376 kb · p 7.6e-14 · regional, not allelic
Overall
CADD	26.4	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 8.47e-05% European (non-Finnish) · 1/1,179,994 alleles

Overall 6.2e-05% 1/1,614,080 alleles · very rare exomes 1/1,461,872 · genomes 0/152,208 · 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: LARGE1
Protein: p.Val697Leu
Coding: c.2089G>T
MANE Select: NM_133642
dbSNP: rs1602190224
Type: single nucleotide variant
Location: chr22:33274609 (GRCh38)
Gene constraint: LOEUF 0.606 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.15 · 4 PDB
Residue 697: a β-strand; the 'glucuronyltransferase activity' region

Full LARGE1 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

LARGE1 p.Val697= Likely benign ★ same residue
LARGE1 p.Arg95Ter Pathogenic ★★ same type
LARGE1 p.Glu509Lys Pathogenic/Likely pathogenic ★★ same type
LARGE1 c.*155C>T Uncertain significance ★★ same type
LARGE1 p.Ala149Ser Uncertain significance ★★ ⚠ same type
LARGE1 p.Ala252Thr Uncertain significance ★★ ⚠ same type
LARGE1 p.Ala252Val Uncertain significance ★★ ⚠ same type
LARGE1 p.Ala478Thr Uncertain significance ★★ ⚠ 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/large1-p-val697leu (accessed [today's date]).

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