Is MACF1 p.Arg600Gln (c.1799G>A) pathogenic?

MACF1 p.Arg600Gln (c.1799G>A) is classified Benign/Likely benign in MACF1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.0802); Rare (popmax 0.218%, nfe); Associated with lissencephaly 9 with complex brainstem malformation.

What condition is associated with MACF1 p.Arg600Gln (c.1799G>A)?

MACF1 p.Arg600Gln (c.1799G>A) is associated with lissencephaly 9 with complex brainstem malformation (ClinVar).

How common is MACF1 p.Arg600Gln (c.1799G>A) in the general population?

MACF1 p.Arg600Gln (c.1799G>A) is rare (popmax 0.218%, nfe) (gnomAD).

What do computational predictors say about MACF1 p.Arg600Gln (c.1799G>A)?

AlphaMissense predicts likely benign (score 0.0802) — an in-silico prediction, not a clinical call.

MACF1 p.Arg600Gln

c.1799G>A · rs139794027 · VCV982710

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0802 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.218%, nfe)

Conditions

lissencephaly 9 with complex brainstem malformation

Computational evidence

Protein change
AlphaMissense	0.0802	likely benign
REVEL	0.357	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.00039 · regional, not allelic
Overall
CADD	24.0	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 R605Q vs ClinVar R600Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.218% European (non-Finnish) · 2,578/1,179,872 alleles

Filtering AF 0.211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.209%

Overall 0.223% 3,595/1,613,532 alleles · rare exomes 3,235/1,461,272 · genomes 360/152,260 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.33%	75
European (non-Finnish)grpmax	0.218%	458
Remaining individualsnot grpmax-eligible	0.146%	687
Admixed American	0.0834%	1,199
African / African-American	0.04%	2,500
Middle Eastern	0.0165%	6,054

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg600Gln
Coding: c.1799G>A
MANE Select: NM_001394062
dbSNP: rs139794027
Type: single nucleotide variant
Location: chr1:39291923 (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-arg600gln (accessed [today's date]).

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