Is MACF1 p.His4883= (c.14649T>C) pathogenic?

MACF1 p.His4883= (c.14649T>C) is classified Benign in MACF1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-15). Common (popmax 7.54%, afr) — too common for a highly-penetrant pathogenic allele; Associated with lissencephaly 9 with complex brainstem malformation.

What condition is associated with MACF1 p.His4883= (c.14649T>C)?

MACF1 p.His4883= (c.14649T>C) is associated with lissencephaly 9 with complex brainstem malformation (ClinVar).

MACF1 p.His4883=

Q: How common is MACF1 p.His4883= (c.14649T>C) in the general population?

MACF1 p.His4883= (c.14649T>C) is common (popmax 7.54%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.14649T>C · rs79901102 · VCV773141

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 7.54%, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.4	GERP -4.5
Overall
CADD	0.047	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.54% African / African-American · 5,649/74,946 alleles

Filtering AF 7.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.31%

Overall 0.417% 6,733/1,613,988 alleles · common exomes 3,556/1,461,860 · genomes 3,177/152,128 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.54%	13
Ashkenazi Jewishnot grpmax-eligible	0.655%	153
Admixed American	0.555%	180
Remaining individualsnot grpmax-eligible	0.552%	181
Middle Eastern	0.33%	303
South Asian	0.0154%	6,505
European (non-Finnish)	0.0149%	6,705
East Asian	0.00223%	44,872
Finnishnot grpmax-eligible	0.00156%	64,022

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.His4883=
Coding: c.14649T>C
MANE Select: NM_001394062
dbSNP: rs79901102
Type: single nucleotide variant
Location: chr1:39387491 (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-his4883 (accessed [today's date]).

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