Is MACF1 p.Gln252= (c.756G>A) pathogenic?

MACF1 p.Gln252= (c.756G>A) is classified Benign in MACF1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Common (popmax 78.5%, sas) — too common for a highly-penetrant pathogenic allele; Associated with lissencephaly 9 with complex brainstem malformation.

What condition is associated with MACF1 p.Gln252= (c.756G>A)?

MACF1 p.Gln252= (c.756G>A) is associated with lissencephaly 9 with complex brainstem malformation (ClinVar).

MACF1 p.Gln252=

Q: How common is MACF1 p.Gln252= (c.756G>A) in the general population?

MACF1 p.Gln252= (c.756G>A) is common (popmax 78.5%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.756G>A · rs2275188 · VCV1264063

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 78.5%, sas) — 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.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.9	GERP -3, phastCons 1
Overall
CADD	9.063	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 78.5% South Asian · 71,459/91,044 alleles

Filtering AF 78% ClinGen BA1/BS1 input FAF95, joint · FAF99 77.8%

Overall 68.6% 1,106,930/1,613,168 alleles · common exomes 1,015,772/1,461,184 · genomes 91,158/151,984 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	78.5%	1
Amishnot grpmax-eligible	78.2%	1
Finnishnot grpmax-eligible	74.6%	1
European (non-Finnish)	69.8%	1
Admixed American	69.4%	1
Ashkenazi Jewishnot grpmax-eligible	68.8%	1
Remaining individualsnot grpmax-eligible	68.3%	1
Middle Eastern	67%	1
East Asian	66.3%	2
African / African-American	33.2%	3

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.Gln252=
Coding: c.756G>A
MANE Select: NM_001394062
dbSNP: rs2275188
Type: single nucleotide variant
Location: chr1:39283249 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Residue 252: an α-helix; the calponin-homology (ch) 2 domain; 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.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-gln252 (accessed [today's date]).

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