Is MACF1 p.Arg12Gln (c.35G>A) pathogenic?

MACF1 p.Arg12Gln (c.35G>A) is classified Conflicting classifications of pathogenicity in MACF1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-09). AlphaMissense: ambiguous (0.3914); Ultra-rare (popmax 0.0298%, nfe); Associated with lissencephaly 9 with complex brainstem malformation.

What condition is associated with MACF1 p.Arg12Gln (c.35G>A)?

MACF1 p.Arg12Gln (c.35G>A) is associated with lissencephaly 9 with complex brainstem malformation (ClinVar).

How common is MACF1 p.Arg12Gln (c.35G>A) in the general population?

MACF1 p.Arg12Gln (c.35G>A) is ultra-rare (popmax 0.0298%, nfe) (gnomAD).

What do computational predictors say about MACF1 p.Arg12Gln (c.35G>A)?

AlphaMissense predicts ambiguous (score 0.3914) — an in-silico prediction, not a clinical call.

MACF1 p.Arg12Gln

c.35G>A · rs200446050 · VCV1314745

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3914 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0298%, nfe)

Conditions

lissencephaly 9 with complex brainstem malformation

Computational evidence

Protein change
AlphaMissense	0.3914	ambiguous
REVEL	0.286	benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0298% European (non-Finnish) · 351/1,179,258 alleles

Filtering AF 0.0272% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0262%

Overall 0.0233% 376/1,612,688 alleles · ultra-rare exomes 354/1,460,536 · genomes 22/152,152 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,290
European (non-Finnish)grpmax	0.0298%	3,360
Remaining individualsnot grpmax-eligible	0.0112%	8,918
East Asian	0.0111%	8,978
African / African-American	0.00401%	24,967
Admixed American	0.00167%	59,942

Ashkenazi Jewish 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.Arg12Gln
Coding: c.35G>A
MANE Select: NM_001394062 · reported on NM_012090
dbSNP: rs200446050
Type: single nucleotide variant
Location: chr1:39084253 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Residue 12: the 'disordered' region; the 'actin-binding' region

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-arg12gln (accessed [today's date]).

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