Is MACF1 p.Arg515His (c.1544G>A) pathogenic?

MACF1 p.Arg515His (c.1544G>A) is classified Uncertain significance in MACF1 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-04-01). AlphaMissense: likely benign (0.1466); Very rare (popmax 0.00667%, amr).

How common is MACF1 p.Arg515His (c.1544G>A) in the general population?

MACF1 p.Arg515His (c.1544G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about MACF1 p.Arg515His (c.1544G>A)?

AlphaMissense predicts likely benign (score 0.1466) — an in-silico prediction, not a clinical call.

MACF1 p.Arg515His

c.1544G>A · rs778551048 · VCV3030308

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1466 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1466	likely benign
REVEL	0.766	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 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.00039 · regional, not allelic
Overall
CADD	24.4	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 R520H vs ClinVar R515H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,998 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00175%

Overall 0.00248% 40/1,613,946 alleles · very rare exomes 36/1,461,886 · genomes 4/152,060 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,999
European (non-Finnish)	0.0028%	35,759
Finnishnot grpmax-eligible	0.00156%	64,000
African / African-American	0.00134%	74,852
South Asian	0.0011%	91,078

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.Arg515His
Coding: c.1544G>A
MANE Select: NM_001394062
dbSNP: rs778551048
Type: single nucleotide variant
Location: chr1:39287321 (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.Arg515Cys Conflicting classifications of pathogenicity ★ ⚠ 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-arg515his (accessed [today's date]).

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