Is MACF1 p.Pro338Thr (c.1012C>A) pathogenic?

MACF1 p.Pro338Thr (c.1012C>A) is classified Likely benign in MACF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-14). AlphaMissense: ambiguous (0.4137); Ultra-rare (popmax 0.0201%, eas); Associated with Inborn genetic diseases.

What condition is associated with MACF1 p.Pro338Thr (c.1012C>A)?

MACF1 p.Pro338Thr (c.1012C>A) is associated with Inborn genetic diseases (ClinVar).

How common is MACF1 p.Pro338Thr (c.1012C>A) in the general population?

MACF1 p.Pro338Thr (c.1012C>A) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about MACF1 p.Pro338Thr (c.1012C>A)?

AlphaMissense predicts ambiguous (score 0.4137) — an in-silico prediction, not a clinical call.

MACF1 p.Pro338Thr

c.1012C>A · VCV3292485

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4137 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4137	ambiguous
REVEL	0.818	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 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 1,691 bp · p 0.0034 · regional, not allelic
Overall
CADD	22.1	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 P343T vs ClinVar P338T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0201% East Asian · 9/44,878 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.00062% 10/1,613,392 alleles · ultra-rare exomes 8/1,461,286 · genomes 2/152,106 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,986
Remaining individualsnot grpmax-eligible	0.0016%	62,460

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.Pro338Thr
Coding: c.1012C>A
MANE Select: NM_001394062
Type: single nucleotide variant
Location: chr1:39284162 (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

Similar variants

MACF1 p.Pro338Leu Uncertain significance ★ same residue
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-pro338thr (accessed [today's date]).

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