Is MACF1 p.Arg515Cys (c.1543C>T) pathogenic?

MACF1 p.Arg515Cys (c.1543C>T) is classified Conflicting classifications of pathogenicity in MACF1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-29). AlphaMissense: likely benign (0.2611); Very rare (popmax 0.00381%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MACF1 p.Arg515Cys (c.1543C>T)?

MACF1 p.Arg515Cys (c.1543C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MACF1 p.Arg515Cys (c.1543C>T) in the general population?

MACF1 p.Arg515Cys (c.1543C>T) is very rare (popmax 0.00381%, nfe) (gnomAD).

What do computational predictors say about MACF1 p.Arg515Cys (c.1543C>T)?

AlphaMissense predicts likely benign (score 0.2611) — an in-silico prediction, not a clinical call.

MACF1 p.Arg515Cys

c.1543C>T · rs375922773 · VCV2158142

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2611 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2611	likely benign
REVEL	0.78	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 4.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.00039 · regional, not allelic
Overall
CADD	24.2	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 R520C vs ClinVar R515C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00381% European (non-Finnish) · 45/1,180,032 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00427% 69/1,614,046 alleles · very rare exomes 62/1,461,886 · genomes 7/152,160 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0676%	1,480
European (non-Finnish)grpmax	0.00381%	26,223
Remaining individualsnot grpmax-eligible	0.0032%	31,245
East Asian	0.00223%	44,900
Admixed American	0.00167%	60,004

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg515Cys
Coding: c.1543C>T
MANE Select: NM_001394062
dbSNP: rs375922773
Type: single nucleotide variant
Location: chr1:39287320 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MACF1 p.Arg515His Uncertain significance ★ ⚠ same residue
MACF1 p.Ala5598Ser Uncertain significance ★★ same condition
MACF1 p.Ala601Pro Uncertain significance ★★ ⚠ same condition
MACF1 p.Arg30Gln Uncertain significance ★★ same condition
MACF1 p.Arg3713Cys Uncertain significance ★★ ⚠ same condition
MACF1 p.Arg4674Cys Uncertain significance ★★ same condition
MACF1 p.Arg5490Gln Uncertain significance ★★ ⚠ same condition
MACF1 p.Arg5875Cys 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-arg515cys (accessed [today's date]).

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