Is MAK p.Pro459Arg (c.1376C>G) pathogenic?

MAK p.Pro459Arg (c.1376C>G) is classified Uncertain significance in MAK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-03). AlphaMissense: likely benign (0.0977); Very rare (popmax 8.47e-05%, nfe).

How common is MAK p.Pro459Arg (c.1376C>G) in the general population?

MAK p.Pro459Arg (c.1376C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about MAK p.Pro459Arg (c.1376C>G)?

AlphaMissense predicts likely benign (score 0.0977) — an in-silico prediction, not a clinical call.

MAK p.Pro459Arg

c.1376C>G · rs2127532782 · VCV1696180

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0977	likely benign
REVEL	0.211	benign-leaning
SaProt	LLR -7.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 0.27, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 66 kb · p 0.0057 · regional, not allelic
Overall
CADD	21.5	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,000 alleles

Overall 6.2e-05% 1/1,614,174 alleles · very rare exomes 1/1,461,846 · genomes 0/152,328 · 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: MAK
Protein: p.Pro459Arg
Coding: c.1376C>G
MANE Select: NM_001242957
dbSNP: rs2127532782
Type: single nucleotide variant
Location: chr6:10784513 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.74
Residue 459: the 'disordered' region

Full MAK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAK c.101+1G>A Likely pathogenic ★★ same type
MAK c.156+2T>C Likely pathogenic ★★ same type
MAK c.831+1G>C Likely pathogenic ★★ same type
MAK c.832-1G>C Likely pathogenic ★★ same type
MAK p.Arg166His Pathogenic ★★ same type
MAK p.Arg272Ter Pathogenic/Likely pathogenic ★★ same type
MAK p.Arg3Ter Pathogenic/Likely pathogenic ★★ same type
MAK p.Asn130His Likely pathogenic ★★ 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/mak-p-pro459arg (accessed [today's date]).

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