Is MACF1 p.Ala4556fs (c.13663_13664dup) pathogenic?

MACF1 p.Ala4556fs (c.1366313664dup) is classified Uncertain significance in MACF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-08). No gnomAD frequency available for this variant; Associated with lissencephaly 9 with complex brainstem malformation.

What condition is associated with MACF1 p.Ala4556fs (c.13663_13664dup)?

MACF1 p.Ala4556fs (c.13663_13664dup) is associated with lissencephaly 9 with complex brainstem malformation (ClinVar).

How common is MACF1 p.Ala4556fs (c.13663_13664dup) in the general population?

MACF1 p.Ala4556fs (c.13663_13664dup) is no gnomAD frequency available for this variant (gnomAD).

MACF1 p.Ala4556fs

c.13663_13664dup · rs2522593863 · VCV2433586

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

lissencephaly 9 with complex brainstem malformation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 56 of 101
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.1	GERP -0.034, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MACF1
Protein: p.Ala4556fs
Coding: c.13663_13664dup
MANE Select: NM_001394062
dbSNP: rs2522593863
Type: Duplication
Location: chr1:39381966 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)

Full MACF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lissencephaly 9 with complex brainstem malformation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MACF1 p.Arg2377fs Likely pathogenic ★ same condition
MACF1 p.Glu110fs Likely pathogenic ★ same condition
MACF1 p.Arg7251Pro Likely pathogenic ★★ same condition
MACF1 p.Arg30Gln Uncertain significance ★★ same condition
MACF1 p.Arg3713Cys Uncertain significance ★★ ⚠ same condition
MACF1 p.Arg6864Gln Uncertain significance ★★ same condition
MACF1 p.Arg7005Trp Uncertain significance ★★ ⚠ same condition
MACF1 p.Glu5190del 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/macf1-p-ala4556fs (accessed [today's date]).

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