Is MACF1 p.Arg6351Ser (c.19053A>T) pathogenic?

MACF1 p.Arg6351Ser (c.19053A>T) is classified Uncertain significance in MACF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-24). AlphaMissense: ambiguous (0.3403); Very rare (popmax 0.0011%, nfe); Associated with lissencephaly 9 with complex brainstem malformation.

What condition is associated with MACF1 p.Arg6351Ser (c.19053A>T)?

MACF1 p.Arg6351Ser (c.19053A>T) is associated with lissencephaly 9 with complex brainstem malformation (ClinVar).

How common is MACF1 p.Arg6351Ser (c.19053A>T) in the general population?

MACF1 p.Arg6351Ser (c.19053A>T) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about MACF1 p.Arg6351Ser (c.19053A>T)?

AlphaMissense predicts ambiguous (score 0.3403) — an in-silico prediction, not a clinical call.

MACF1 p.Arg6351Ser

c.19053A>T · rs1306003144 · VCV1698800

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3403 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Conditions

lissencephaly 9 with complex brainstem malformation

Computational evidence

Protein change
AlphaMissense	0.3403	ambiguous
REVEL	0.102	moderately benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -2.9, phastCons 0.99
Regional constraint	o/e 0.87	unconstrained · MANE · 93 kb · p 4.8e-14 · regional, not allelic
Overall
CADD	15.38	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 R6250S vs ClinVar R6351S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,180,032 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000805% 13/1,614,214 alleles · very rare exomes 13/1,461,886 · genomes 0/152,328 · joint denominator

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.Arg6351Ser
Coding: c.19053A>T
MANE Select: NM_001394062
dbSNP: rs1306003144
Type: single nucleotide variant
Location: chr1:39442516 (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-arg6351ser (accessed [today's date]).

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