Is MACF1 p.Cys7236Phe (c.21707G>T) pathogenic?

MACF1 p.Cys7236Phe (c.21707G>T) is classified Pathogenic in MACF1 (ClinVar, Single submitter, 4 submitters; last evaluated 2022-05-04). AlphaMissense: likely pathogenic (0.9966); Absent from gnomAD v4.1; Associated with lissencephaly spectrum disorders.

What condition is associated with MACF1 p.Cys7236Phe (c.21707G>T)?

MACF1 p.Cys7236Phe (c.21707G>T) is associated with lissencephaly spectrum disorders, lissencephaly 9 with complex brainstem malformation (ClinVar).

How common is MACF1 p.Cys7236Phe (c.21707G>T) in the general population?

MACF1 p.Cys7236Phe (c.21707G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MACF1 p.Cys7236Phe (c.21707G>T)?

AlphaMissense predicts likely pathogenic (score 0.9966) — an in-silico prediction, not a clinical call.

MACF1 p.Cys7236Phe

c.21707G>T · rs1557668270 · VCV586948

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9966 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

lissencephaly spectrum disorders

Computational evidence

Protein change
AlphaMissense	0.9966	likely pathogenic ✓ concordant with ClinVar · top 1% in MACF1
REVEL	0.917	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 19 kb · p 1.3e-24 · regional, not allelic
Overall
CADD	25.8	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 C7135F vs ClinVar C7236F) — 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.Cys7236Phe
Coding: c.21707G>T
MANE Select: NM_001394062
dbSNP: rs1557668270
Type: single nucleotide variant
Location: chr1:39463640 (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 spectrum disorders — 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.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-cys7236phe (accessed [today's date]).

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