Is MACF1 p.Arg4451Cys (c.13351C>T) pathogenic?

MACF1 p.Arg4451Cys (c.13351C>T) is classified Likely benign in MACF1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0992); Rare (popmax 0.215%, afr).

How common is MACF1 p.Arg4451Cys (c.13351C>T) in the general population?

MACF1 p.Arg4451Cys (c.13351C>T) is rare (popmax 0.215%, afr) (gnomAD).

What do computational predictors say about MACF1 p.Arg4451Cys (c.13351C>T)?

AlphaMissense predicts likely benign (score 0.0992) — an in-silico prediction, not a clinical call.

MACF1 p.Arg4451Cys

c.13351C>T · rs79990239 · VCV2083040

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0992 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.215%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0992	likely benign
REVEL	0.258	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.3, phastCons 0.93
Regional constraint	o/e 0.87	unconstrained · MANE · 93 kb · p 4.8e-14 · regional, not allelic
Overall
CADD	23.4	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 R4456C vs ClinVar R4451C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.215% African / African-American · 161/74,888 alleles

Filtering AF 0.188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.178%

Overall 0.0221% 356/1,612,966 alleles · rare exomes 259/1,460,992 · genomes 97/151,974 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.215%	465
European (non-Finnish)	0.0153%	6,553
Remaining individualsnot grpmax-eligible	0.0144%	6,940
Admixed American	0.00836%	11,958
East Asian	0.00223%	44,816

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.Arg4451Cys
Coding: c.13351C>T
MANE Select: NM_001394062
dbSNP: rs79990239
Type: single nucleotide variant
Location: chr1:39379277 (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.Arg4451His Uncertain significance ★ ⚠ 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-arg4451cys (accessed [today's date]).

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