Is MACF1 p.Pro4534= (c.13602C>T) pathogenic?

MACF1 p.Pro4534= (c.13602C>T) is classified Likely benign in MACF1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-11-08). Very rare (popmax 0.000339%, nfe); Associated with MACF1-related disorder.

What condition is associated with MACF1 p.Pro4534= (c.13602C>T)?

MACF1 p.Pro4534= (c.13602C>T) is associated with MACF1-related disorder (ClinVar).

How common is MACF1 p.Pro4534= (c.13602C>T) in the general population?

MACF1 p.Pro4534= (c.13602C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

MACF1 p.Pro4534=

c.13602C>T · rs750535518 · VCV3044666

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

MACF1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.2	GERP -0.57
Overall
CADD	5.904	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,696 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,472 alleles · very rare exomes 4/1,461,202 · genomes 0/152,270 · 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.Pro4534=
Coding: c.13602C>T
MANE Select: NM_001394062
dbSNP: rs750535518
Type: single nucleotide variant
Location: chr1:39380327 (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

MACF1-related disorder

Similar variants

MACF1 p.Pro4534Ala Uncertain significance ★ same residue
MACF1 c.15817-8796A>G Uncertain significance ★ same condition
MACF1 c.3945+5G>C Conflicting classifications of pathogenicity ★ same condition
MACF1 p.Ala3863Thr Uncertain significance ★ ⚠ same condition
MACF1 p.Ala4286Val Conflicting classifications of pathogenicity ★ ⚠ same condition
MACF1 p.Arg6753Trp Conflicting classifications of pathogenicity ★ ⚠ same condition
MACF1 p.Asn4460Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
MACF1 p.Asn4550Thr 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-pro4534 (accessed [today's date]).

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