Is MACF1 p.Arg7271His (c.21812G>A) pathogenic?

MACF1 p.Arg7271His (c.21812G>A) is classified Uncertain significance in MACF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-09). AlphaMissense: likely pathogenic (0.9382); Very rare (popmax 0.000254%, nfe).

How common is MACF1 p.Arg7271His (c.21812G>A) in the general population?

MACF1 p.Arg7271His (c.21812G>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about MACF1 p.Arg7271His (c.21812G>A)?

AlphaMissense predicts likely pathogenic (score 0.9382) — an in-silico prediction, not a clinical call.

MACF1 p.Arg7271His

c.21812G>A · VCV3702123

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9382 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Computational evidence

Protein change
AlphaMissense	0.9382	likely pathogenic · top 8% in MACF1
REVEL	0.532	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 19 kb · p 1.3e-24 · regional, not allelic
Overall
CADD	25.2	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 R7164H vs ClinVar R7271H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,026 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,134 alleles · very rare exomes 3/1,461,872 · genomes 0/152,262 · 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.Arg7271His
Coding: c.21812G>A
MANE Select: NM_001394062
Type: single nucleotide variant
Location: chr1:39468655 (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-arg7271his (accessed [today's date]).

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