Is MACF1 p.Glu248Asp (c.744G>T) pathogenic?

MACF1 p.Glu248Asp (c.744G>T) is classified Conflicting classifications of pathogenicity in MACF1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-12-26). AlphaMissense: likely benign (0.0933); Ultra-rare (popmax 0.028%, afr); Associated with lissencephaly 9 with complex brainstem malformation.

What condition is associated with MACF1 p.Glu248Asp (c.744G>T)?

MACF1 p.Glu248Asp (c.744G>T) is associated with lissencephaly 9 with complex brainstem malformation (ClinVar).

How common is MACF1 p.Glu248Asp (c.744G>T) in the general population?

MACF1 p.Glu248Asp (c.744G>T) is ultra-rare (popmax 0.028%, afr) (gnomAD).

What do computational predictors say about MACF1 p.Glu248Asp (c.744G>T)?

AlphaMissense predicts likely benign (score 0.0933) — an in-silico prediction, not a clinical call.

MACF1 p.Glu248Asp

c.744G>T · rs371386732 · VCV1325546

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0933 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, afr)

Conditions

lissencephaly 9 with complex brainstem malformation

Computational evidence

Protein change
AlphaMissense	0.0933	likely benign
REVEL	0.615	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -1.1, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 31 kb · p 2.8e-10 · regional, not allelic
Overall
CADD	18.46	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM E253D vs ClinVar E248D) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.028% African / African-American · 21/75,036 alleles

Filtering AF 0.0187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00142% 23/1,614,086 alleles · ultra-rare exomes 15/1,461,814 · genomes 8/152,272 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.028%	3,573
Admixed American	0.00167%	60,016
South Asian	0.0011%	91,064

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.Glu248Asp
Coding: c.744G>T
MANE Select: NM_001394062
dbSNP: rs371386732
Type: single nucleotide variant
Location: chr1:39283237 (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.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-glu248asp (accessed [today's date]).

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