Is MACF1 p.Pro461Leu (c.1382C>T) pathogenic?

MACF1 p.Pro461Leu (c.1382C>T) is classified Conflicting classifications of pathogenicity in MACF1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-23). AlphaMissense: likely benign (0.0695); Very rare (popmax 0.00659%, sas); Associated with Inborn genetic diseases.

What condition is associated with MACF1 p.Pro461Leu (c.1382C>T)?

MACF1 p.Pro461Leu (c.1382C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MACF1 p.Pro461Leu (c.1382C>T) in the general population?

MACF1 p.Pro461Leu (c.1382C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about MACF1 p.Pro461Leu (c.1382C>T)?

AlphaMissense predicts likely benign (score 0.0695) — an in-silico prediction, not a clinical call.

MACF1 p.Pro461Leu

c.1382C>T · rs138060421 · VCV2543583

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0695 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0695	likely benign
REVEL	0.422	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.00039 · regional, not allelic
Overall
CADD	22.0	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 P466L vs ClinVar P461L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,066 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00229% 37/1,613,896 alleles · very rare exomes 29/1,461,818 · genomes 8/152,078 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,178
African / African-American	0.00534%	18,713
East Asian	0.00446%	22,441
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)	0.00195%	51,304

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.Pro461Leu
Coding: c.1382C>T
MANE Select: NM_001394062
dbSNP: rs138060421
Type: single nucleotide variant
Location: chr1:39285632 (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-pro461leu (accessed [today's date]).

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