Is LCA5 p.Phe253= (c.759C>T) pathogenic?

LCA5 p.Phe253= (c.759C>T) is classified Likely benign in LCA5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). Rare (popmax 0.112%, sas); Associated with Leber congenital amaurosis 5.

What condition is associated with LCA5 p.Phe253= (c.759C>T)?

LCA5 p.Phe253= (c.759C>T) is associated with Leber congenital amaurosis 5 (ClinVar).

How common is LCA5 p.Phe253= (c.759C>T) in the general population?

LCA5 p.Phe253= (c.759C>T) is rare (popmax 0.112%, sas) (gnomAD).

How is Leber congenital amaurosis inherited?

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

LCA5 p.Phe253=

c.759C>T · rs528612334 · VCV741980

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.112%, sas)

Conditions

Leber congenital amaurosis 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP -2.1, phastCons 1
Overall
CADD	6.845	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.112% South Asian · 102/91,040 alleles

Filtering AF 0.0944% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0878%

Overall 0.00651% 105/1,613,466 alleles · rare exomes 98/1,461,292 · genomes 7/152,174 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.112%	893
Remaining individualsnot grpmax-eligible	0.0048%	20,828

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: LCA5
Protein: p.Phe253=
Coding: c.759C>T
MANE Select: NM_001122769
dbSNP: rs528612334
Type: single nucleotide variant
Location: chr6:79493712 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.05

Full LCA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Leber congenital amaurosis 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Leber congenital amaurosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

LCA5 c.190+1G>A Pathogenic/Likely pathogenic ★★ same condition
LCA5 c.721-1G>A Pathogenic/Likely pathogenic ★★ same condition
LCA5 c.721-2A>T Pathogenic/Likely pathogenic ★★ same condition
LCA5 c.858+1G>C Likely pathogenic ★★ same condition
LCA5 p.Ala319Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
LCA5 p.Arg218Ter Pathogenic/Likely pathogenic ★★ same condition
LCA5 p.Arg255Ter Pathogenic ★★ same condition
LCA5 p.Arg280Ter 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/lca5-p-phe253 (accessed [today's date]).

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