Is MACF1 p.Ala7022Pro (c.21064G>C) pathogenic?

MACF1 p.Ala7022Pro (c.21064G>C) is classified Conflicting classifications of pathogenicity in MACF1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-08). AlphaMissense: likely pathogenic (0.716); Very rare (popmax 0.00934%, afr); Associated with Inborn genetic diseases.

What condition is associated with MACF1 p.Ala7022Pro (c.21064G>C)?

MACF1 p.Ala7022Pro (c.21064G>C) is associated with Inborn genetic diseases (ClinVar).

How common is MACF1 p.Ala7022Pro (c.21064G>C) in the general population?

MACF1 p.Ala7022Pro (c.21064G>C) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about MACF1 p.Ala7022Pro (c.21064G>C)?

AlphaMissense predicts likely pathogenic (score 0.716) — an in-silico prediction, not a clinical call.

MACF1 p.Ala7022Pro

c.21064G>C · rs142006710 · VCV1314461

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.716 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.716	likely pathogenic
REVEL	0.232	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.3	GERP 0.88, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 18 kb · p 1.1e-08 · 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 A6921P vs ClinVar A7022P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00934% African / African-American · 7/74,918 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000496% 8/1,613,698 alleles · very rare exomes 3/1,461,522 · genomes 5/152,176 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,703
Remaining individualsnot grpmax-eligible	0.0016%	62,464

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.Ala7022Pro
Coding: c.21064G>C
MANE Select: NM_001394062
dbSNP: rs142006710
Type: single nucleotide variant
Location: chr1:39455086 (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.Ala7022Thr Conflicting classifications of pathogenicity ★ ⚠ 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-ala7022pro (accessed [today's date]).

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