Is ABCA4 p.Ser84fs (c.247_250dup) pathogenic?

ABCA4 p.Ser84fs (c.247250dup) is classified Pathogenic/Likely pathogenic in ABCA4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-10). Very rare (popmax 0.00167%, amr); Associated with cone-rod dystrophy 3.

What condition is associated with ABCA4 p.Ser84fs (c.247_250dup)?

ABCA4 p.Ser84fs (c.247_250dup) is associated with cone-rod dystrophy 3, severe early-childhood-onset retinal dystrophy (ClinVar).

How common is ABCA4 p.Ser84fs (c.247_250dup) in the general population?

ABCA4 p.Ser84fs (c.247_250dup) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Cone rod dystrophy inherited?

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

ABCA4 p.Ser84fs

c.247_250dup · rs1005271380 · VCV854791

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

cone-rod dystrophy 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 50
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.34	GERP -3.5, phastCons 0.11
Overall
CADD	26.7	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 0.00167% Admixed American · 1/60,010 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000682% 11/1,614,066 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,010
European (non-Finnish)	0.000847%	118,003

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: ABCA4
Protein: p.Ser84fs
Coding: c.247_250dup
MANE Select: NM_000350
dbSNP: rs1005271380
Type: Duplication
Location: chr1:94111489 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 84: a β-strand; a disulfide bond; a UniProt-annotated variant site (in stgd1; uncertain significance); a UniProt-annotated variant site (in cord3; uncertain significance)

Full ABCA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cone-rod dystrophy 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: severe early-childhood-onset retinal dystrophy

For Cone rod dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

ABCA4 p.Ala1791fs Pathogenic ★★★ same condition
ABCA4 p.Ser1071fs Pathogenic ★★★ same condition
ABCA4 p.Asn99fs Pathogenic ★★ same condition
ABCA4 p.Gly1110fs Pathogenic/Likely pathogenic ★★ same condition
ABCA4 p.Val2236fs Pathogenic/Likely pathogenic ★★ same condition
ABCA4 c.1356+4dup Conflicting classifications of pathogenicity ★ same condition
ABCA4 p.Ser84= Likely benign ★ same residue
ABCA4 c.1937+1G>A 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/abca4-p-ser84fs (accessed [today's date]).

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