Is RD3 p.Ser170Phe (c.509C>T) pathogenic?

RD3 p.Ser170Phe (c.509C>T) is classified Uncertain significance in RD3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-12). AlphaMissense: likely pathogenic (0.9111); Ultra-rare (popmax 0.0494%, mid); Associated with Leber congenital amaurosis 12.

What condition is associated with RD3 p.Ser170Phe (c.509C>T)?

RD3 p.Ser170Phe (c.509C>T) is associated with Leber congenital amaurosis 12 (ClinVar).

How common is RD3 p.Ser170Phe (c.509C>T) in the general population?

RD3 p.Ser170Phe (c.509C>T) is ultra-rare (popmax 0.0494%, mid) (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.Ser170Phe (c.509C>T)?

AlphaMissense predicts likely pathogenic (score 0.9111) — an in-silico prediction, not a clinical call.

RD3 p.Ser170Phe

c.509C>T · rs776821754 · VCV1043566

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9111 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Leber congenital amaurosis 12

Computational evidence

Protein change
AlphaMissense	0.9111	likely pathogenic · top 4% in RD3
REVEL	0.332	indeterminate
SaProt	LLR -8.19	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.7	GERP 1.3, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,376 bp · p 0.68 · regional, not allelic
Overall
CADD	26.4	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 0.0494% Middle Eastern · 3/6,076 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.0031% 50/1,612,280 alleles · ultra-rare exomes 48/1,460,022 · genomes 2/152,258 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0494%	2,025
Admixed American	0.00501%	19,973
Remaining individualsnot grpmax-eligible	0.00481%	20,783
European (non-Finnish)	0.00331%	30,246
South Asian	0.0022%	45,435

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.Ser170Phe
Coding: c.509C>T
MANE Select: NM_001164688
dbSNP: rs776821754
Type: single nucleotide variant
Location: chr1:211479115 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.99 · 1 PDB
Residue 170: the 'disordered' region

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 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
RD3 p.Arg182Gln 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-ser170phe (accessed [today's date]).

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