Is LCA5 p.Pro65fs (c.194del) pathogenic?

LCA5 p.Pro65fs (c.194del) is classified Pathogenic in LCA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-08). Very rare (popmax 0.0022%, sas).

How common is LCA5 p.Pro65fs (c.194del) in the general population?

LCA5 p.Pro65fs (c.194del) is very rare (popmax 0.0022%, sas) (gnomAD).

LCA5 p.Pro65fs

c.194del · rs2533440718 · VCV2780093

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP -0.8, phastCons 0.63

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,058 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,613,320 alleles · very rare exomes 2/1,461,192 · genomes 0/152,128 · 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: LCA5
Protein: p.Pro65fs
Coding: c.194del
MANE Select: NM_001122769
dbSNP: rs2533440718
Type: Deletion
Location: chr6:79513738 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.05
Residue 65: the 'disordered' region

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

Similar variants

LCA5 p.Pro65Ala Uncertain significance ★ ⚠ same residue
LCA5 p.Pro65= Likely benign ★ same residue
LCA5 p.Ala184fs Pathogenic/Likely pathogenic ★★ same type
LCA5 p.Ala425fs Pathogenic/Likely pathogenic ★★ same type
LCA5 p.Asn251fs Pathogenic/Likely pathogenic ★★ same type
LCA5 p.Asp269fs Likely pathogenic ★★ same type
LCA5 p.Cys353_Tyr354insTer Pathogenic ★★ same type
LCA5 p.Glu13fs Pathogenic/Likely pathogenic ★★ 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/lca5-p-pro65fs (accessed [today's date]).

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