Is MACF1 p.Ala5820Pro (c.17458G>C) pathogenic?

MACF1 p.Ala5820Pro (c.17458G>C) is classified Likely benign in MACF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-30). AlphaMissense: likely pathogenic (0.9679); Ultra-rare (popmax 0.019%, sas); Associated with Inborn genetic diseases.

What condition is associated with MACF1 p.Ala5820Pro (c.17458G>C)?

MACF1 p.Ala5820Pro (c.17458G>C) is associated with Inborn genetic diseases (ClinVar).

How common is MACF1 p.Ala5820Pro (c.17458G>C) in the general population?

MACF1 p.Ala5820Pro (c.17458G>C) is ultra-rare (popmax 0.019%, sas) (gnomAD).

What do computational predictors say about MACF1 p.Ala5820Pro (c.17458G>C)?

AlphaMissense predicts likely pathogenic (score 0.9679) — an in-silico prediction, not a clinical call.

MACF1 p.Ala5820Pro

c.17458G>C · rs774738714 · VCV2609087

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9679 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.019%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9679	likely pathogenic · top 6% in MACF1
REVEL	0.391	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.26 · evaluated, not missing
Pangolin	Δ0.26	gain · loss 0.19 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 8.6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 93 kb · p 4.8e-14 · regional, not allelic
Overall
CADD	33.0	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 A5716P vs ClinVar A5820P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.019% South Asian · 17/89,348 alleles

Filtering AF 0.0121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00994%

Overall 0.00144% 23/1,594,092 alleles · ultra-rare exomes 19/1,441,922 · genomes 4/152,170 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.019%	5,256
Remaining individualsnot grpmax-eligible	0.00487%	20,553
East Asian	0.00224%	44,596
European (non-Finnish)	0.000172%	582,421

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.Ala5820Pro
Coding: c.17458G>C
MANE Select: NM_001394062
dbSNP: rs774738714
Type: single nucleotide variant
Location: chr1:39433048 (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-ala5820pro (accessed [today's date]).

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