Is MACF1 p.Ser3958Pro (c.11872T>C) pathogenic?

MACF1 p.Ser3958Pro (c.11872T>C) is classified Benign/Likely benign in MACF1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0948); Rare (popmax 0.802%, afr); Associated with Inborn genetic diseases.

What condition is associated with MACF1 p.Ser3958Pro (c.11872T>C)?

MACF1 p.Ser3958Pro (c.11872T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MACF1 p.Ser3958Pro (c.11872T>C) in the general population?

MACF1 p.Ser3958Pro (c.11872T>C) is rare (popmax 0.802%, afr) (gnomAD).

What do computational predictors say about MACF1 p.Ser3958Pro (c.11872T>C)?

AlphaMissense predicts likely benign (score 0.0948) — an in-silico prediction, not a clinical call.

MACF1 p.Ser3958Pro

c.11872T>C · rs77561254 · VCV2071224

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0948 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.802%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0948	likely benign
REVEL	0.267	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 4.2	GERP 2.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 93 kb · p 4.8e-14 · regional, not allelic
Overall
CADD	18.24	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 S3963P vs ClinVar S3958P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.802% African / African-American · 601/74,958 alleles

Filtering AF 0.749% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.728%

Overall 0.0397% 641/1,613,956 alleles · rare exomes 316/1,461,848 · genomes 325/152,108 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.802%	125
Remaining individualsnot grpmax-eligible	0.0336%	2,977
Admixed American	0.0233%	4,285
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.000339%	294,992

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.Ser3958Pro
Coding: c.11872T>C
MANE Select: NM_001394062
dbSNP: rs77561254
Type: single nucleotide variant
Location: chr1:39357822 (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.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-ser3958pro (accessed [today's date]).

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