Is MACF1 p.Arg2813Ser (c.8439A>T) pathogenic?

MACF1 p.Arg2813Ser (c.8439A>T) is classified Likely benign in MACF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1928); Rare (popmax 0.548%, nfe).

How common is MACF1 p.Arg2813Ser (c.8439A>T) in the general population?

MACF1 p.Arg2813Ser (c.8439A>T) is rare (popmax 0.548%, nfe) (gnomAD).

What do computational predictors say about MACF1 p.Arg2813Ser (c.8439A>T)?

AlphaMissense predicts likely benign (score 0.1928) — an in-silico prediction, not a clinical call.

MACF1 p.Arg2813Ser

c.8439A>T · rs80235954 · VCV2498401

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1928 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.548%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1928	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP -0.53, phastCons 0.57
Regional constraint	o/e 0.96	unconstrained · MANE · 11 kb · p 0.078 · regional, not allelic
Overall
CADD	7.401	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 R2818S vs ClinVar R2813S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.548% European (non-Finnish) · 6,468/1,179,982 alleles

Filtering AF 0.537% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.532%

Overall 0.428% 6,906/1,614,060 alleles · rare exomes 6,483/1,461,752 · genomes 423/152,308 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.548%	182
Remaining individualsnot grpmax-eligible	0.242%	414
African / African-American	0.112%	893
Admixed American	0.102%	984
South Asian	0.09%	1,111
Finnishnot grpmax-eligible	0.0843%	1,186
Middle Eastern	0.0495%	2,021
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,865

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.Arg2813Ser
Coding: c.8439A>T
MANE Select: NM_001394062
dbSNP: rs80235954
Type: single nucleotide variant
Location: chr1:39335027 (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.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
MACF1 p.Arg5490Gln 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-arg2813ser (accessed [today's date]).

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