Is RD3 p.Arg8Trp (c.22C>T) pathogenic?

RD3 p.Arg8Trp (c.22C>T) is classified Uncertain significance in RD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-05). AlphaMissense: likely benign (0.1446); Very rare (popmax 0.005%, amr); Associated with Leber congenital amaurosis 12.

What condition is associated with RD3 p.Arg8Trp (c.22C>T)?

RD3 p.Arg8Trp (c.22C>T) is associated with Leber congenital amaurosis 12 (ClinVar).

How common is RD3 p.Arg8Trp (c.22C>T) in the general population?

RD3 p.Arg8Trp (c.22C>T) is very rare (popmax 0.005%, amr) (gnomAD).

How is Leber congenital amaurosis inherited?

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

What do computational predictors say about RD3 p.Arg8Trp (c.22C>T)?

AlphaMissense predicts likely benign (score 0.1446) — an in-silico prediction, not a clinical call.

RD3 p.Arg8Trp

c.22C>T · rs142307843 · VCV1026526

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1446 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Leber congenital amaurosis 12

Computational evidence

Protein change
AlphaMissense	0.1446	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	LLR -10.78	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.4	GERP 0.92, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,376 bp · p 0.68 · regional, not allelic
Overall
CADD	23.7	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 0.005% Admixed American · 3/60,008 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000992% 16/1,612,908 alleles · very rare exomes 15/1,460,690 · genomes 1/152,218 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00801%	12,478
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804
Admixed Americangrpmax	0.005%	20,003
African / African-American	0.00133%	74,916
European (non-Finnish)	0.000424%	236,009

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: RD3
Protein: p.Arg8Trp
Coding: c.22C>T
MANE Select: NM_001164688
dbSNP: rs142307843
Type: single nucleotide variant
Location: chr1:211481394 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.99 · 1 PDB

Full RD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Leber congenital amaurosis 12 — 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

RD3 p.Arg8Gln Uncertain significance ★ ⚠ same residue
RD3 c.296+1G>T Pathogenic/Likely pathogenic ★★ same condition
RD3 p.Arg38Ter Pathogenic ★★ same condition
RD3 p.Tyr60Ter Pathogenic ★★ same condition
RD3 c.-572G>A Uncertain significance ★★ same condition
RD3 c.*1277G>A Uncertain significance ★★ same condition
RD3 p.Ala135Val Uncertain significance ★★ ⚠ same condition
RD3 p.Arg15Trp Uncertain significance ★★ ⚠ 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/rd3-p-arg8trp (accessed [today's date]).

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