Is MACF1 p.Ser4373= (c.13119T>C) pathogenic?

MACF1 p.Ser4373= (c.13119T>C) is classified Benign in MACF1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-30). Common (popmax 9.74%, afr) — too common for a highly-penetrant pathogenic allele; Associated with lissencephaly 9 with complex brainstem malformation.

What condition is associated with MACF1 p.Ser4373= (c.13119T>C)?

MACF1 p.Ser4373= (c.13119T>C) is associated with lissencephaly 9 with complex brainstem malformation (ClinVar).

MACF1 p.Ser4373=

Q: How common is MACF1 p.Ser4373= (c.13119T>C) in the general population?

MACF1 p.Ser4373= (c.13119T>C) is common (popmax 9.74%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.13119T>C · rs80197726 · VCV1250500

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 9.74%, 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.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.9	GERP -0.21, phastCons 1
Overall
CADD	10.28	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.74% African / African-American · 7,297/74,898 alleles

Filtering AF 9.56% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.48%

Overall 4.44% 71,642/1,612,414 alleles · common exomes 63,187/1,460,324 · genomes 8,455/152,090 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.74%	10
Amishnot grpmax-eligible	8.02%	12
South Asian	5.63%	18
European (non-Finnish)	4.34%	23
Finnishnot grpmax-eligible	4.19%	24
Remaining individualsnot grpmax-eligible	4.14%	24
Admixed American	2.91%	34
Ashkenazi Jewishnot grpmax-eligible	2.74%	37
Middle Eastern	2.61%	38
East Asian	0.0201%	4,984

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.Ser4373=
Coding: c.13119T>C
MANE Select: NM_001394062
dbSNP: rs80197726
Type: single nucleotide variant
Location: chr1:39372502 (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.Ser4373Asn Uncertain significance ★ ⚠ 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-ser4373 (accessed [today's date]).

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