Is MACF1 p.Ser3915Pro (c.11743T>C) pathogenic?

MACF1 p.Ser3915Pro (c.11743T>C) is classified Benign/Likely benign in MACF1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.0908); Rare (popmax 0.157%, nfe); Associated with lissencephaly 9 with complex brainstem malformation.

What condition is associated with MACF1 p.Ser3915Pro (c.11743T>C)?

MACF1 p.Ser3915Pro (c.11743T>C) is associated with lissencephaly 9 with complex brainstem malformation (ClinVar).

How common is MACF1 p.Ser3915Pro (c.11743T>C) in the general population?

MACF1 p.Ser3915Pro (c.11743T>C) is rare (popmax 0.157%, nfe) (gnomAD).

What do computational predictors say about MACF1 p.Ser3915Pro (c.11743T>C)?

AlphaMissense predicts likely benign (score 0.0908) — an in-silico prediction, not a clinical call.

MACF1 p.Ser3915Pro

c.11743T>C · rs148356076 · VCV2049971

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0908 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.157%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

lissencephaly 9 with complex brainstem malformation

Computational evidence

Protein change
AlphaMissense	0.0908	likely benign
REVEL	0.112	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 0.69	GERP 1, phastCons 0.15
Regional constraint	o/e 0.87	unconstrained · MANE · 93 kb · p 4.8e-14 · regional, not allelic
Overall
CADD	19.12	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 S3920P vs ClinVar S3915P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.157% European (non-Finnish) · 1,850/1,180,004 alleles

Filtering AF 0.151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.148%

Overall 0.123% 1,982/1,614,084 alleles · rare exomes 1,861/1,461,878 · genomes 121/152,206 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.157%	638
Remaining individualsnot grpmax-eligible	0.107%	933
Admixed American	0.045%	2,223
African / African-American	0.0427%	2,344
Finnishnot grpmax-eligible	0.00937%	10,670

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.Ser3915Pro
Coding: c.11743T>C
MANE Select: NM_001394062
dbSNP: rs148356076
Type: single nucleotide variant
Location: chr1:39357693 (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

lissencephaly 9 with complex brainstem malformation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MACF1 p.Arg7251Pro Likely pathogenic ★★ same condition
MACF1 p.Arg30Gln Uncertain significance ★★ same condition
MACF1 p.Arg3713Cys Uncertain significance ★★ ⚠ same condition
MACF1 p.Arg6864Gln Uncertain significance ★★ same condition
MACF1 p.Arg7005Trp Uncertain significance ★★ ⚠ same condition
MACF1 p.Glu6915Lys Uncertain significance ★★ same condition
MACF1 p.Ile380Thr Uncertain significance ★★ ⚠ same condition
MACF1 p.Leu6865Phe 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-ser3915pro (accessed [today's date]).

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