Is MACF1 p.Glu110fs (c.328dup) pathogenic?

MACF1 p.Glu110fs (c.328dup) is classified Likely pathogenic in MACF1 (ClinVar, Single submitter, 1 submitter). Very rare (popmax 0.00368%, sas); Associated with lissencephaly 9 with complex brainstem malformation.

What condition is associated with MACF1 p.Glu110fs (c.328dup)?

MACF1 p.Glu110fs (c.328dup) is associated with lissencephaly 9 with complex brainstem malformation (ClinVar).

How common is MACF1 p.Glu110fs (c.328dup) in the general population?

MACF1 p.Glu110fs (c.328dup) is very rare (popmax 0.00368%, sas) (gnomAD).

MACF1 p.Glu110fs

c.328dup · VCV4849882

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00368%, sas)

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 4 of 101
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.3	GERP 2.9, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00368% South Asian · 3/81,548 alleles

Filtering AF 0.000977% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000471%

Overall 0.000329% 5/1,520,070 alleles · very rare exomes 5/1,367,728 · genomes 0/152,342 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00368%	27,183
Remaining individualsnot grpmax-eligible	0.00338%	29,611

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: MACF1
Protein: p.Glu110fs
Coding: c.328dup
MANE Select: NM_001394062
Type: Duplication
Location: chr1:39251910 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Residue 110: the 'disordered' region; the calponin-homology (ch) 1 domain; an α-helix; the 'actin-binding' region

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.Ala4556fs Uncertain significance ★ 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-glu110fs (accessed [today's date]).

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