Is LCA5L p.Ser596Arg (c.1788C>G) pathogenic?

LCA5L p.Ser596Arg (c.1788C>G) is classified Uncertain significance in LCA5L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-24). AlphaMissense: ambiguous (0.5269); Ultra-rare (popmax 0.0307%, afr).

How common is LCA5L p.Ser596Arg (c.1788C>G) in the general population?

LCA5L p.Ser596Arg (c.1788C>G) is ultra-rare (popmax 0.0307%, afr) (gnomAD).

What do computational predictors say about LCA5L p.Ser596Arg (c.1788C>G)?

AlphaMissense predicts ambiguous (score 0.5269) — an in-silico prediction, not a clinical call.

LCA5L p.Ser596Arg

c.1788C>G · VCV3866603

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5269 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.5269	ambiguous
REVEL	0.037	moderately benign-leaning
SaProt	LLR -2.62	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4	GERP 1.4, phastCons 0.98
Regional constraint	o/e 0.88	unconstrained · MANE · 23 kb · p 0.00069 · regional, not allelic
Overall
CADD	19.85	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 0.0307% African / African-American · 23/74,928 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.00173% 28/1,614,064 alleles · ultra-rare exomes 17/1,461,870 · genomes 11/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0307%	3,258
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000254%	393,345

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: LCA5L
Protein: p.Ser596Arg
Coding: c.1788C>G
MANE Select: NM_152505
Type: single nucleotide variant
Location: chr21:39406107 (GRCh38)

Full LCA5L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/lca5l-p-ser596arg (accessed [today's date]).

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