Is MACF1 p.Ala686Val (c.2057C>T) pathogenic?

MACF1 p.Ala686Val (c.2057C>T) is classified Uncertain significance in MACF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-21). AlphaMissense: likely benign (0.1043); Very rare (popmax 0.00267%, afr).

How common is MACF1 p.Ala686Val (c.2057C>T) in the general population?

MACF1 p.Ala686Val (c.2057C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about MACF1 p.Ala686Val (c.2057C>T)?

AlphaMissense predicts likely benign (score 0.1043) — an in-silico prediction, not a clinical call.

MACF1 p.Ala686Val

c.2057C>T · VCV4769087

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1043 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1043	likely benign
REVEL	0.242	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.99 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.00039 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A691V vs ClinVar A686V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,044 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,928 alleles · very rare exomes 2/1,461,632 · genomes 0/152,296 · joint denominator

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.Ala686Val
Coding: c.2057C>T
MANE Select: NM_001394062
Type: single nucleotide variant
Location: chr1:39293522 (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-ala686val (accessed [today's date]).

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