Is MACF1 p.Met4232Ile (c.12696G>A) pathogenic?

MACF1 p.Met4232Ile (c.12696G>A) is classified Likely benign in MACF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-24). AlphaMissense: likely benign (0.265); Very rare (popmax 0.00833%, amr).

How common is MACF1 p.Met4232Ile (c.12696G>A) in the general population?

MACF1 p.Met4232Ile (c.12696G>A) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about MACF1 p.Met4232Ile (c.12696G>A)?

AlphaMissense predicts likely benign (score 0.265) — an in-silico prediction, not a clinical call.

MACF1 p.Met4232Ile

c.12696G>A · rs761267912 · VCV2786593

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.265 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.265	likely benign
REVEL	0.073	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 7.5	GERP 2.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 93 kb · p 4.8e-14 · regional, not allelic
Overall
CADD	21.4	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 M4237I vs ClinVar M4232I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,018 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.00031% 5/1,614,168 alleles · very rare exomes 5/1,461,890 · genomes 0/152,278 · joint denominator

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.Met4232Ile
Coding: c.12696G>A
MANE Select: NM_001394062
dbSNP: rs761267912
Type: single nucleotide variant
Location: chr1:39361602 (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.Met4232Val Likely benign ★ same residue
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

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-met4232ile (accessed [today's date]).

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