Is MACF1 p.Cys14Arg (c.40T>C) pathogenic?

MACF1 p.Cys14Arg (c.40T>C) is classified Uncertain significance in MACF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-03). AlphaMissense: ambiguous (0.4331); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with MACF1 p.Cys14Arg (c.40T>C)?

MACF1 p.Cys14Arg (c.40T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MACF1 p.Cys14Arg (c.40T>C) in the general population?

MACF1 p.Cys14Arg (c.40T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about MACF1 p.Cys14Arg (c.40T>C)?

AlphaMissense predicts ambiguous (score 0.4331) — an in-silico prediction, not a clinical call.

MACF1 p.Cys14Arg

c.40T>C · VCV4102063

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4331 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4331	ambiguous
REVEL	0.305	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.6, phastCons 1
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,060 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,612,536 alleles · very rare exomes 3/1,460,416 · genomes 0/152,120 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,060
European (non-Finnish)	0.00017%	589,543

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.Cys14Arg
Coding: c.40T>C
MANE Select: NM_001394062 · reported on NM_012090
Type: single nucleotide variant
Location: chr1:39084258 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Residue 14: the 'disordered' region; the 'actin-binding' region

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.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
MACF1 p.Arg6864Gln 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-cys14arg (accessed [today's date]).

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