Is MACF1 p.Met4352Val (c.13054A>G) pathogenic?

MACF1 p.Met4352Val (c.13054A>G) is classified Benign in MACF1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0592); Common (popmax 21.3%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with lissencephaly 9 with complex brainstem malformation.

What condition is associated with MACF1 p.Met4352Val (c.13054A>G)?

MACF1 p.Met4352Val (c.13054A>G) is associated with lissencephaly 9 with complex brainstem malformation (ClinVar).

What do computational predictors say about MACF1 p.Met4352Val (c.13054A>G)?

AlphaMissense predicts likely benign (score 0.0592) — an in-silico prediction, not a clinical call.

MACF1 p.Met4352Val

Q: How common is MACF1 p.Met4352Val (c.13054A>G) in the general population?

MACF1 p.Met4352Val (c.13054A>G) is common (popmax 21.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.13054A>G · rs2296172 · VCV1232730

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0592 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 21.3%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

lissencephaly 9 with complex brainstem malformation

Computational evidence

Protein change
AlphaMissense	0.0592	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	Δ0.63	donor gain · deltas
Constraint at this position
Conservation	phyloP -0.032	GERP -1.8
Regional constraint	o/e 0.87	unconstrained · MANE · 93 kb · p 4.8e-14 · regional, not allelic
Overall
CADD	17.54	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 M4357V vs ClinVar M4352V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 21.3% European (non-Finnish) · 251,797/1,179,466 alleles

Filtering AF 21.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.2%

Overall 19.6% 316,993/1,613,338 alleles · common exomes 292,667/1,461,116 · genomes 24,326/152,222 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	23.4%	4
European (non-Finnish)grpmax	21.3%	5
Admixed American	20.9%	5
Finnishnot grpmax-eligible	19.8%	5
Remaining individualsnot grpmax-eligible	18.4%	5
East Asian	16.8%	6
Middle Eastern	15.9%	6
South Asian	11.2%	9
Amishnot grpmax-eligible	9.98%	10
African / African-American	3.68%	27

Ashkenazi Jewish 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.Met4352Val
Coding: c.13054A>G
MANE Select: NM_001394062
dbSNP: rs2296172
Type: single nucleotide variant
Location: chr1:39370145 (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-met4352val (accessed [today's date]).

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