Is MACF1 p.Ile5263Val (c.15787A>G) pathogenic?

MACF1 p.Ile5263Val (c.15787A>G) is classified Likely benign in MACF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-13). AlphaMissense: likely benign (0.0573); Very rare (popmax 0.00955%, afr).

How common is MACF1 p.Ile5263Val (c.15787A>G) in the general population?

MACF1 p.Ile5263Val (c.15787A>G) is very rare (popmax 0.00955%, afr) (gnomAD).

What do computational predictors say about MACF1 p.Ile5263Val (c.15787A>G)?

AlphaMissense predicts likely benign (score 0.0573) — an in-silico prediction, not a clinical call.

MACF1 p.Ile5263Val

c.15787A>G · VCV3341685

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0573 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00955%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0573	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; 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 -0.025	GERP -3.6
Regional constraint	o/e 0.87	unconstrained · MANE · 93 kb · p 4.8e-14 · regional, not allelic
Overall
CADD	0.906	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 I5268V vs ClinVar I5263V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00955% African / African-American · 7/73,280 alleles

Filtering AF 0.00446% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00314%

Overall 0.00139% 22/1,579,368 alleles · very rare exomes 22/1,427,030 · genomes 0/152,338 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00955%	10,469
Remaining individualsnot grpmax-eligible	0.00164%	60,968
European (non-Finnish)	0.0012%	83,217

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.Ile5263Val
Coding: c.15787A>G
MANE Select: NM_001394062
Type: single nucleotide variant
Location: chr1:39388629 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)

Full MACF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MACF1 p.Arg7251Pro Likely pathogenic ★★ same type
MACF1 p.Ala5598Ser Uncertain significance ★★ same type
MACF1 p.Ala601Pro Uncertain significance ★★ ⚠ same type
MACF1 p.Arg1196Gln Uncertain significance ★★ ⚠ same type
MACF1 p.Arg30Gln Uncertain significance ★★ same type
MACF1 p.Arg3713Cys Uncertain significance ★★ ⚠ same type
MACF1 p.Arg4674Cys Uncertain significance ★★ same type
MACF1 p.Arg5490Gln Uncertain significance ★★ ⚠ same type

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-ile5263val (accessed [today's date]).

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