Is MACF1 p.Ser1308= (c.3924G>A) pathogenic?

MACF1 p.Ser1308= (c.3924G>A) is classified Benign/Likely benign in MACF1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-19). Rare (popmax 0.108%, nfe); Associated with lissencephaly 9 with complex brainstem malformation.

What condition is associated with MACF1 p.Ser1308= (c.3924G>A)?

MACF1 p.Ser1308= (c.3924G>A) is associated with lissencephaly 9 with complex brainstem malformation (ClinVar).

How common is MACF1 p.Ser1308= (c.3924G>A) in the general population?

MACF1 p.Ser1308= (c.3924G>A) is rare (popmax 0.108%, nfe) (gnomAD).

MACF1 p.Ser1308=

c.3924G>A · rs150560748 · VCV1635650

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.108%, nfe)

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	0.131	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.7	GERP -4.3
Overall
CADD	1.913	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.108% European (non-Finnish) · 1,276/1,179,234 alleles

Filtering AF 0.103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.147% 2,368/1,612,476 alleles · rare exomes 2,070/1,460,188 · genomes 298/152,288 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.34%	75
Remaining individualsnot grpmax-eligible	0.13%	771
European (non-Finnish)grpmax	0.108%	924
Admixed American	0.0818%	1,223
South Asian	0.0814%	1,229
Ashkenazi Jewishnot grpmax-eligible	0.0812%	1,232
African / African-American	0.016%	6,249
East Asian	0.00446%	22,413

Finnish 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: MACF1
Protein: p.Ser1308=
Coding: c.3924G>A
MANE Select: NM_001394062
dbSNP: rs150560748
Type: single nucleotide variant
Location: chr1:39318594 (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.Ser1308Leu Benign/Likely benign ★★ same residue
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

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-ser1308 (accessed [today's date]).

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