Is LCA5 p.Arg35Ter (c.103C>T) pathogenic?

LCA5 p.Arg35Ter (c.103C>T) is classified Pathogenic/Likely pathogenic in LCA5 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-02-18). Very rare (popmax 0.00102%, nfe); Associated with Leber congenital amaurosis 5.

What condition is associated with LCA5 p.Arg35Ter (c.103C>T)?

LCA5 p.Arg35Ter (c.103C>T) is associated with Leber congenital amaurosis 5, inherited retinal dystrophy (ClinVar).

How common is LCA5 p.Arg35Ter (c.103C>T) in the general population?

LCA5 p.Arg35Ter (c.103C>T) is very rare (popmax 0.00102%, nfe) (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.Arg35Ter

c.103C>T · rs748370008 · VCV844114

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Conditions

Leber congenital amaurosis 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 8
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 0.028, phastCons 0.25
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00102% European (non-Finnish) · 12/1,179,996 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000867% 14/1,614,034 alleles · very rare exomes 14/1,461,850 · genomes 0/152,184 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,251
European (non-Finnish)grpmax	0.00102%	98,333

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg35Ter
Coding: c.103C>T
MANE Select: NM_001122769
dbSNP: rs748370008
Type: single nucleotide variant
Location: chr6:79518792 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.05
Residue 35: the 'disordered' region

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

Also linked: inherited retinal dystrophy

For Leber congenital amaurosis (Orphanet):

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

Similar variants

LCA5 p.Arg35Gln Uncertain significance ★ ⚠ same residue
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

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-arg35ter (accessed [today's date]).

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