Is ABCD4 p.Cys593fs (c.1779_1780del) pathogenic?

ABCD4 p.Cys593fs (c.17791780del) is classified Uncertain significance in ABCD4 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-03-09). Very rare (popmax 0.0022%, sas).

How common is ABCD4 p.Cys593fs (c.1779_1780del) in the general population?

ABCD4 p.Cys593fs (c.1779_1780del) is very rare (popmax 0.0022%, sas) (gnomAD).

ABCD4 p.Cys593fs

c.1779_1780del · rs1566906720 · VCV592037

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (19 of 19) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.7	GERP 1.2, phastCons 1
Overall
CADD	34.0	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 0.0022% South Asian · 2/91,094 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000186% 3/1,614,156 alleles · very rare exomes 1/1,461,882 · genomes 2/152,274 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
South Asiangrpmax	0.0022%	45,547

Ashkenazi Jewish 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: ABCD4
Protein: p.Cys593fs
Coding: c.1779_1780del
MANE Select: NM_005050
dbSNP: rs1566906720
Type: Microsatellite
Location: chr14:74286502 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 593: the abc transporter domain

Full ABCD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCD4 p.Ser416fs Pathogenic ★★ same type
ABCD4 p.Ser533fs Likely pathogenic ★ same type
ABCD4 p.Glu556fs Conflicting classifications of pathogenicity ★ same type
ABCD4 p.Leu82fs Conflicting classifications of pathogenicity ★ same type
ABCD4 c.1456+67_1456+68del Benign ★ same type
ABCD4 c.1636+234CTTTT[3] Benign ★ same type
ABCD4 c.1636+273_1636+274del Benign ★ same type
ABCD4 c.543-17CT[3] Likely benign ★ 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/abcd4-p-cys593fs (accessed [today's date]).

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