Is MACF1 p.Asp3674Val (c.11021A>T) pathogenic?

MACF1 p.Asp3674Val (c.11021A>T) is classified Benign in MACF1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-06-04). AlphaMissense: likely benign (0.2846); Rare (popmax 0.189%, eas).

How common is MACF1 p.Asp3674Val (c.11021A>T) in the general population?

MACF1 p.Asp3674Val (c.11021A>T) is rare (popmax 0.189%, eas) (gnomAD).

What do computational predictors say about MACF1 p.Asp3674Val (c.11021A>T)?

AlphaMissense predicts likely benign (score 0.2846) — an in-silico prediction, not a clinical call.

MACF1 p.Asp3674Val

c.11021A>T · rs59084124 · VCV3057571

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2846 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.189%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.2846	likely benign
REVEL	0.128	moderately 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 7.9	GERP 0.74, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 93 kb · p 4.8e-14 · regional, not allelic
Overall
CADD	23.7	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 D3679V vs ClinVar D3674V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.189% East Asian · 85/44,866 alleles

Filtering AF 0.157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.145%

Overall 0.00818% 132/1,614,084 alleles · rare exomes 108/1,461,800 · genomes 24/152,284 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.189%	528
Remaining individualsnot grpmax-eligible	0.0208%	4,808
South Asian	0.0187%	5,357
Middle Eastern	0.0165%	6,062
Admixed American	0.00167%	60,022
European (non-Finnish)	0.00127%	78,664

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.Asp3674Val
Coding: c.11021A>T
MANE Select: NM_001394062
dbSNP: rs59084124
Type: single nucleotide variant
Location: chr1:39350840 (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-asp3674val (accessed [today's date]).

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