Is MACF1 p.Ser5299Arg (c.15895A>C) pathogenic?

MACF1 p.Ser5299Arg (c.15895A>C) is classified Likely benign in MACF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-18). AlphaMissense: likely pathogenic (0.9687); Ultra-rare (popmax 0.0167%, amr); Associated with Inborn genetic diseases.

What condition is associated with MACF1 p.Ser5299Arg (c.15895A>C)?

MACF1 p.Ser5299Arg (c.15895A>C) is associated with Inborn genetic diseases (ClinVar).

How common is MACF1 p.Ser5299Arg (c.15895A>C) in the general population?

MACF1 p.Ser5299Arg (c.15895A>C) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about MACF1 p.Ser5299Arg (c.15895A>C)?

AlphaMissense predicts likely pathogenic (score 0.9687) — an in-silico prediction, not a clinical call.

MACF1 p.Ser5299Arg

c.15895A>C · rs774845983 · VCV2212730

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9687 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9687	likely pathogenic · top 5% in MACF1
REVEL	0.487	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 93 kb · p 4.8e-14 · regional, not allelic
Overall
CADD	22.4	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 S5304R vs ClinVar S5299R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Admixed American · 10/60,008 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.000743% 12/1,614,024 alleles · ultra-rare exomes 9/1,461,796 · genomes 3/152,228 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	6,001
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	8.47e-05%	1,179,976

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.Ser5299Arg
Coding: c.15895A>C
MANE Select: NM_001394062
dbSNP: rs774845983
Type: single nucleotide variant
Location: chr1:39422452 (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-ser5299arg (accessed [today's date]).

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