Is MACF1 p.Leu653Phe (c.1957C>T) pathogenic?

MACF1 p.Leu653Phe (c.1957C>T) is classified Likely pathogenic in MACF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-21). AlphaMissense: ambiguous (0.4851); Absent from gnomAD v4.1; Associated with lissencephaly 9 with complex brainstem malformation.

What condition is associated with MACF1 p.Leu653Phe (c.1957C>T)?

MACF1 p.Leu653Phe (c.1957C>T) is associated with lissencephaly 9 with complex brainstem malformation (ClinVar).

How common is MACF1 p.Leu653Phe (c.1957C>T) in the general population?

MACF1 p.Leu653Phe (c.1957C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MACF1 p.Leu653Phe (c.1957C>T)?

AlphaMissense predicts ambiguous (score 0.4851) — an in-silico prediction, not a clinical call.

MACF1 p.Leu653Phe

c.1957C>T · rs2148401189 · VCV1676542

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4851 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

lissencephaly 9 with complex brainstem malformation

Computational evidence

Protein change
AlphaMissense	0.4851	ambiguous
REVEL	0.703	pathogenic-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.00039 · 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 L658F vs ClinVar L653F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MACF1
Protein: p.Leu653Phe
Coding: c.1957C>T
MANE Select: NM_001394062
dbSNP: rs2148401189
Type: single nucleotide variant
Location: chr1:39292808 (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.Leu653Pro 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-leu653phe (accessed [today's date]).

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