Is ABCA1 p.Lys422fs (c.1265del) pathogenic?

ABCA1 p.Lys422fs (c.1265del) is classified Pathogenic in ABCA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-16). Very rare (popmax 0.00133%, afr).

How common is ABCA1 p.Lys422fs (c.1265del) in the general population?

ABCA1 p.Lys422fs (c.1265del) is very rare (popmax 0.00133%, afr) (gnomAD).

ABCA1 p.Lys422fs

c.1265del · VCV4715168

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

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 11 of 50
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.4	GERP 1, phastCons 1
Overall
CADD	28.5	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 0.00133% African / African-American · 1/75,058 alleles

Overall 0.000657% 1/152,310 alleles · very rare

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: ABCA1
Protein: p.Lys422fs
Coding: c.1265del
MANE Select: NM_005502
Type: Deletion
Location: chr9:104837026 (GRCh38)
Gene constraint: LOEUF 0.563 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.50 · 7 PDB
Residue 422: an α-helix

Full ABCA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCA1 p.Lys422Arg Uncertain significance ★ ⚠ same residue
ABCA1 c.5383-3del Benign ★★ same type
ABCA1 c.5383-4_5383-3del Benign/Likely benign ★★ same type
ABCA1 c.5637-4del Benign/Likely benign ★★ same type
ABCA1 c.6309-16_6309-15del Likely benign ★★ same type
ABCA1 c.6309-20del Likely benign ★★ same type
ABCA1 c.721-10del Benign ★★ same type
ABCA1 p.Asn141fs Pathogenic ★ same type

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/abca1-p-lys422fs (accessed [today's date]).

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