Is ABCA4 p.Asp645Tyr (c.1933G>T) pathogenic?

ABCA4 p.Asp645Tyr (c.1933G>T) is classified Pathogenic in ABCA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-05). AlphaMissense: likely pathogenic (0.9289); Very rare (popmax 0.000271%, nfe); Associated with retinitis pigmentosa.

What condition is associated with ABCA4 p.Asp645Tyr (c.1933G>T)?

ABCA4 p.Asp645Tyr (c.1933G>T) is associated with retinitis pigmentosa (ClinVar).

How common is ABCA4 p.Asp645Tyr (c.1933G>T) in the general population?

ABCA4 p.Asp645Tyr (c.1933G>T) is very rare (popmax 0.000271%, nfe) (gnomAD).

How is Retinitis pigmentosa inherited?

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

What do computational predictors say about ABCA4 p.Asp645Tyr (c.1933G>T)?

AlphaMissense predicts likely pathogenic (score 0.9289) — an in-silico prediction, not a clinical call.

ABCA4 p.Asp645Tyr

c.1933G>T · rs61749418 · VCV1998012

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9289 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000271%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.9289	likely pathogenic ✓ concordant with ClinVar · top 7% in ABCA4
REVEL	0.928	moderately pathogenic-leaning
SaProt	LLR -11.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	26.5	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 0.000271% European (non-Finnish) · 3/1,108,722 alleles

Filtering AF 7.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.00167% 25/1,501,068 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0421%	2,375
European (non-Finnish)grpmax	0.000271%	369,574

Finnish 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: ABCA4
Protein: p.Asp645Tyr
Coding: c.1933G>T
MANE Select: NM_000350
dbSNP: rs61749418
Type: single nucleotide variant
Location: chr1:94062581 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 645: a UniProt-annotated variant site (in cord3; uncertain significance); a UniProt-annotated variant site (in stgd1; uncertain significance); a UniProt-annotated variant site (found in a patient with chorioretinal atrophy; uncertain significance); a UniProt-annotated variant site (in stgd1); a β-strand; a disulfide bond

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

Disease context

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ABCA4 p.Asp645Asn Pathogenic ★★ ⚠ same residue
ABCA4 p.Asp645Gly Likely pathogenic ★ same residue
ABCA4 p.Asp645= Likely benign ★ same residue
ABCA4 c.5460+1G>A Pathogenic ★★★ same condition
ABCA4 c.5461-10T>C Pathogenic ★★★ same condition
ABCA4 p.Ala967Val Likely pathogenic ★★★ ⚠ same condition
ABCA4 p.Arg2139Trp Pathogenic ★★★ same condition
ABCA4 p.Arg408Ter 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-asp645tyr (accessed [today's date]).

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