Is LCA5 p.Arg290Ser (c.870A>C) pathogenic?

LCA5 p.Arg290Ser (c.870A>C) is classified Uncertain significance in LCA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-08). AlphaMissense: likely pathogenic (0.9565); Very rare (popmax 0.00176%, amr).

How common is LCA5 p.Arg290Ser (c.870A>C) in the general population?

LCA5 p.Arg290Ser (c.870A>C) is very rare (popmax 0.00176%, amr) (gnomAD).

What do computational predictors say about LCA5 p.Arg290Ser (c.870A>C)?

AlphaMissense predicts likely pathogenic (score 0.9565) — an in-silico prediction, not a clinical call.

LCA5 p.Arg290Ser

c.870A>C · rs777434118 · VCV2135532

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9565 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9565	likely pathogenic · top 2% in LCA5
REVEL	0.422	indeterminate
SaProt	LLR -8.34	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 1.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 32 kb · p 0.58 · regional, not allelic
Overall
CADD	23.1	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 0.00176% Admixed American · 1/56,844 alleles

Overall 6.57e-05% 1/1,521,632 alleles · very rare exomes 1/1,369,504 · 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.Arg290Ser
Coding: c.870A>C
MANE Select: NM_001122769
dbSNP: rs777434118
Type: single nucleotide variant
Location: chr6:79492636 (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

Similar variants

LCA5 p.Arg290= Likely benign ★ same residue
LCA5 c.190+1G>A Pathogenic/Likely pathogenic ★★ same type
LCA5 c.721-1G>A Pathogenic/Likely pathogenic ★★ same type
LCA5 c.721-2A>T Pathogenic/Likely pathogenic ★★ same type
LCA5 c.858+1G>C Likely pathogenic ★★ same type
LCA5 p.Ala319Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
LCA5 p.Arg218Ter Pathogenic/Likely pathogenic ★★ same type
LCA5 p.Arg255Ter 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-arg290ser (accessed [today's date]).

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