Is MACF1 p.Ala6458Pro (c.19372G>C) pathogenic?

MACF1 p.Ala6458Pro (c.19372G>C) is classified Likely benign in MACF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: ambiguous (0.4909); Ultra-rare (popmax 0.044%, afr); Associated with Inborn genetic diseases.

What condition is associated with MACF1 p.Ala6458Pro (c.19372G>C)?

MACF1 p.Ala6458Pro (c.19372G>C) is associated with Inborn genetic diseases (ClinVar).

How common is MACF1 p.Ala6458Pro (c.19372G>C) in the general population?

MACF1 p.Ala6458Pro (c.19372G>C) is ultra-rare (popmax 0.044%, afr) (gnomAD).

What do computational predictors say about MACF1 p.Ala6458Pro (c.19372G>C)?

AlphaMissense predicts ambiguous (score 0.4909) — an in-silico prediction, not a clinical call.

MACF1 p.Ala6458Pro

c.19372G>C · VCV4102052

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4909 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.044%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4909	ambiguous
REVEL	0.444	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 0.86, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 18 kb · p 1.1e-08 · regional, not allelic
Overall
CADD	23.2	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 A6357P vs ClinVar A6458P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.044% African / African-American · 33/74,924 alleles

Filtering AF 0.0322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0281%

Overall 0.00217% 35/1,613,686 alleles · ultra-rare exomes 25/1,461,482 · genomes 10/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.044%	2,270
Admixed American	0.00167%	59,976
Remaining individualsnot grpmax-eligible	0.0016%	62,468

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.Ala6458Pro
Coding: c.19372G>C
MANE Select: NM_001394062
Type: single nucleotide variant
Location: chr1:39443515 (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.Ala6458Val Likely benign ★ same residue
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

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-ala6458pro (accessed [today's date]).

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