Is MACF1 p.Ile6583Val (c.19747A>G) pathogenic?

MACF1 p.Ile6583Val (c.19747A>G) is classified Uncertain significance in MACF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-30). AlphaMissense: likely benign (0.091); Ultra-rare (popmax 0.0165%, mid); Associated with Spectraplakinopathy type I.

What condition is associated with MACF1 p.Ile6583Val (c.19747A>G)?

MACF1 p.Ile6583Val (c.19747A>G) is associated with Spectraplakinopathy type I (ClinVar).

How common is MACF1 p.Ile6583Val (c.19747A>G) in the general population?

MACF1 p.Ile6583Val (c.19747A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about MACF1 p.Ile6583Val (c.19747A>G)?

AlphaMissense predicts likely benign (score 0.091) — an in-silico prediction, not a clinical call.

MACF1 p.Ile6583Val

c.19747A>G · rs745399595 · VCV983272

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.091 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Spectraplakinopathy type I

Computational evidence

Protein change
AlphaMissense	0.091	likely benign
REVEL	0.786	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ REVEL calls this damaging; AlphaMissense does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 18 kb · p 1.1e-08 · regional, not allelic
Overall
CADD	21.3	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 I6482V vs ClinVar I6583V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00112% 18/1,614,208 alleles · ultra-rare exomes 17/1,461,872 · genomes 1/152,336 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.00333%	30,007
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)	0.0011%	90,772
South Asian	0.0011%	91,084

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.Ile6583Val
Coding: c.19747A>G
MANE Select: NM_001394062
dbSNP: rs745399595
Type: single nucleotide variant
Location: chr1:39447573 (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

Spectraplakinopathy type I

Similar variants

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
MACF1 p.Asp5139Gly 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-ile6583val (accessed [today's date]).

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