Is MACF1 p.Arg4563Gln (c.13688G>A) pathogenic?

MACF1 p.Arg4563Gln (c.13688G>A) is classified Likely benign in MACF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-11). AlphaMissense: likely benign (0.1342); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with MACF1 p.Arg4563Gln (c.13688G>A)?

MACF1 p.Arg4563Gln (c.13688G>A) is associated with Inborn genetic diseases (ClinVar).

How common is MACF1 p.Arg4563Gln (c.13688G>A) in the general population?

MACF1 p.Arg4563Gln (c.13688G>A) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about MACF1 p.Arg4563Gln (c.13688G>A)?

AlphaMissense predicts likely benign (score 0.1342) — an in-silico prediction, not a clinical call.

MACF1 p.Arg4563Gln

c.13688G>A · VCV4102049

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1342 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1342	likely benign
REVEL	0.566	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 93 kb · p 4.8e-14 · 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 R4568Q vs ClinVar R4563Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,910 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00322% 52/1,613,812 alleles · very rare exomes 49/1,461,680 · genomes 3/152,132 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,621
African / African-Americangrpmax	0.004%	24,970
European (non-Finnish)	0.00364%	27,442
Finnishnot grpmax-eligible	0.00313%	31,913

Remaining individuals 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.Arg4563Gln
Coding: c.13688G>A
MANE Select: NM_001394062
Type: single nucleotide variant
Location: chr1:39381992 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MACF1 p.Ala5598Ser Uncertain significance ★★ same condition
MACF1 p.Ala601Pro Uncertain significance ★★ ⚠ same condition
MACF1 p.Arg30Gln Uncertain significance ★★ same condition
MACF1 p.Arg3713Cys Uncertain significance ★★ ⚠ same condition
MACF1 p.Arg4674Cys Uncertain significance ★★ same condition
MACF1 p.Arg5490Gln Uncertain significance ★★ ⚠ same condition
MACF1 p.Arg5875Cys Uncertain significance ★★ same condition
MACF1 p.Arg6864Gln 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-arg4563gln (accessed [today's date]).

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