Is MACF1 p.Glu1232= (c.3696G>A) pathogenic?

MACF1 p.Glu1232= (c.3696G>A) is classified Benign in MACF1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-28). Common (popmax 10.5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with lissencephaly 9 with complex brainstem malformation.

What condition is associated with MACF1 p.Glu1232= (c.3696G>A)?

MACF1 p.Glu1232= (c.3696G>A) is associated with lissencephaly 9 with complex brainstem malformation (ClinVar).

MACF1 p.Glu1232=

Q: How common is MACF1 p.Glu1232= (c.3696G>A) in the general population?

MACF1 p.Glu1232= (c.3696G>A) is common (popmax 10.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3696G>A · rs74066738 · VCV1246325

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 10.5%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

lissencephaly 9 with complex brainstem malformation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.311	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -1.5, phastCons 1
Overall
CADD	6.79	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.5% African / African-American · 7,851/74,992 alleles

Filtering AF 10.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.2%

Overall 0.589% 9,514/1,614,030 alleles · common exomes 4,970/1,461,768 · genomes 4,544/152,262 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.5%	10
Admixed American	0.855%	117
Remaining individualsnot grpmax-eligible	0.83%	120
Middle Eastern	0.582%	172
Ashkenazi Jewishnot grpmax-eligible	0.223%	449
European (non-Finnish)	0.0431%	2,323
South Asian	0.0242%	4,140

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.Glu1232=
Coding: c.3696G>A
MANE Select: NM_001394062
dbSNP: rs74066738
Type: single nucleotide variant
Location: chr1:39317321 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Residue 1232: the 'disordered' 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.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.Glu6915Lys Uncertain significance ★★ same condition
MACF1 p.Ile380Thr Uncertain significance ★★ ⚠ same condition
MACF1 p.Leu6865Phe 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-glu1232 (accessed [today's date]).

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