Is MACF1 p.Ser5474Pro (c.16420T>C) pathogenic?

MACF1 p.Ser5474Pro (c.16420T>C) is classified Uncertain significance in MACF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-06). AlphaMissense: likely pathogenic (0.9421); Very rare (popmax 0.00133%, afr); Associated with lissencephaly 9 with complex brainstem malformation.

What condition is associated with MACF1 p.Ser5474Pro (c.16420T>C)?

MACF1 p.Ser5474Pro (c.16420T>C) is associated with lissencephaly 9 with complex brainstem malformation (ClinVar).

How common is MACF1 p.Ser5474Pro (c.16420T>C) in the general population?

MACF1 p.Ser5474Pro (c.16420T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about MACF1 p.Ser5474Pro (c.16420T>C)?

AlphaMissense predicts likely pathogenic (score 0.9421) — an in-silico prediction, not a clinical call.

MACF1 p.Ser5474Pro

c.16420T>C · VCV3541842

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9421 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

lissencephaly 9 with complex brainstem malformation

Computational evidence

Protein change
AlphaMissense	0.9421	likely pathogenic · top 8% in MACF1
REVEL	0.301	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 93 kb · p 4.8e-14 · regional, not allelic
Overall
CADD	22.6	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 S5479P vs ClinVar S5474P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,046 alleles

Overall 6.2e-05% 1/1,614,122 alleles · very rare exomes 1/1,461,830 · genomes 0/152,292 · joint denominator

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.Ser5474Pro
Coding: c.16420T>C
MANE Select: NM_001394062
Type: single nucleotide variant
Location: chr1:39427558 (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-ser5474pro (accessed [today's date]).

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