Is MACF1 p.Val4559Phe (c.13675G>T) pathogenic?

MACF1 p.Val4559Phe (c.13675G>T) is classified Benign/Likely benign in MACF1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-07-01). AlphaMissense: likely benign (0.1264); Rare (popmax 0.586%, eas); Associated with Inborn genetic diseases.

What condition is associated with MACF1 p.Val4559Phe (c.13675G>T)?

MACF1 p.Val4559Phe (c.13675G>T) is associated with Inborn genetic diseases, lissencephaly 9 with complex brainstem malformation (ClinVar).

How common is MACF1 p.Val4559Phe (c.13675G>T) in the general population?

MACF1 p.Val4559Phe (c.13675G>T) is rare (popmax 0.586%, eas) (gnomAD).

What do computational predictors say about MACF1 p.Val4559Phe (c.13675G>T)?

AlphaMissense predicts likely benign (score 0.1264) — an in-silico prediction, not a clinical call.

MACF1 p.Val4559Phe

c.13675G>T · rs187137636 · VCV2062211

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1264 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.586%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1264	likely benign
REVEL	0.125	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 6.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 93 kb · p 4.8e-14 · regional, not allelic
Overall
CADD	21.8	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 V4564F vs ClinVar V4559F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.586% East Asian · 263/44,886 alleles

Filtering AF 0.528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.505%

Overall 0.0282% 455/1,614,008 alleles · rare exomes 398/1,461,708 · genomes 57/152,300 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.586%	171
Ashkenazi Jewishnot grpmax-eligible	0.368%	272
Remaining individualsnot grpmax-eligible	0.0544%	1,838
South Asian	0.0154%	6,506
African / African-American	0.008%	12,506
European (non-Finnish)	0.00246%	40,689

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.Val4559Phe
Coding: c.13675G>T
MANE Select: NM_001394062
dbSNP: rs187137636
Type: single nucleotide variant
Location: chr1:39381979 (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

Also linked: lissencephaly 9 with complex brainstem malformation

Similar variants

MACF1 p.Arg7251Pro Likely pathogenic ★★ same condition
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

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-val4559phe (accessed [today's date]).

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