Is MACF1 p.Ala738Val (c.2213C>T) pathogenic?

MACF1 p.Ala738Val (c.2213C>T) is classified Uncertain significance in MACF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-17). AlphaMissense: ambiguous (0.4549); Very rare (popmax 0.00178%, nfe).

How common is MACF1 p.Ala738Val (c.2213C>T) in the general population?

MACF1 p.Ala738Val (c.2213C>T) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about MACF1 p.Ala738Val (c.2213C>T)?

AlphaMissense predicts ambiguous (score 0.4549) — an in-silico prediction, not a clinical call.

MACF1 p.Ala738Val

c.2213C>T · VCV4705463

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4549 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4549	ambiguous
REVEL	0.824	moderately pathogenic-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.00039 · regional, not allelic
Overall
CADD	25.2	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 A743V vs ClinVar A738V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00178% European (non-Finnish) · 21/1,179,992 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00167% 27/1,613,942 alleles · very rare exomes 22/1,461,830 · genomes 5/152,112 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00781%	12,802
European (non-Finnish)grpmax	0.00178%	56,190
Remaining individualsnot grpmax-eligible	0.0016%	62,484

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala738Val
Coding: c.2213C>T
MANE Select: NM_001394062
Type: single nucleotide variant
Location: chr1:39295104 (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-ala738val (accessed [today's date]).

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