Is MACF1 p.Pro388Leu (c.1163C>T) pathogenic?

MACF1 p.Pro388Leu (c.1163C>T) is classified Uncertain significance in MACF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-05-19). AlphaMissense: likely benign (0.1438); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with MACF1 p.Pro388Leu (c.1163C>T)?

MACF1 p.Pro388Leu (c.1163C>T) is associated with Inborn genetic diseases, lissencephaly 9 with complex brainstem malformation (ClinVar).

How common is MACF1 p.Pro388Leu (c.1163C>T) in the general population?

MACF1 p.Pro388Leu (c.1163C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about MACF1 p.Pro388Leu (c.1163C>T)?

AlphaMissense predicts likely benign (score 0.1438) — an in-silico prediction, not a clinical call.

MACF1 p.Pro388Leu

c.1163C>T · rs750656239 · VCV1341866

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1438 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1438	likely benign
REVEL	0.437	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 1,691 bp · p 0.0034 · regional, not allelic
Overall
CADD	23.1	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 P393L vs ClinVar P388L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,992 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000434% 7/1,614,008 alleles · very rare exomes 6/1,461,880 · genomes 1/152,128 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,997
European (non-Finnish)	0.000339%	295,009

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.Pro388Leu
Coding: c.1163C>T
MANE Select: NM_001394062
dbSNP: rs750656239
Type: single nucleotide variant
Location: chr1:39285114 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: lissencephaly 9 with complex brainstem malformation

Similar variants

MACF1 p.Arg7251Pro Likely pathogenic ★★ same condition
MACF1 p.Ala5598Ser Uncertain significance ★★ same condition
MACF1 p.Ala601Pro Uncertain significance ★★ ⚠ same condition
MACF1 p.Arg30Gln Uncertain significance ★★ same condition
MACF1 p.Arg3713Cys Uncertain significance ★★ ⚠ same condition
MACF1 p.Arg4674Cys Uncertain significance ★★ same condition
MACF1 p.Arg5490Gln Uncertain significance ★★ ⚠ same condition
MACF1 p.Arg5875Cys 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-pro388leu (accessed [today's date]).

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