Is MAX p.Ser45Asn (c.134G>A) pathogenic?

MAX p.Ser45Asn (c.134G>A) is classified Uncertain significance in MAX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-04). AlphaMissense: ambiguous (0.4827); Very rare (popmax 8.49e-05%, nfe); Associated with hereditary pheochromocytoma-paraganglioma.

What condition is associated with MAX p.Ser45Asn (c.134G>A)?

MAX p.Ser45Asn (c.134G>A) is associated with hereditary pheochromocytoma-paraganglioma, hereditary neoplastic syndrome (ClinVar).

How common is MAX p.Ser45Asn (c.134G>A) in the general population?

MAX p.Ser45Asn (c.134G>A) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

How is Hereditary pheochromocytoma-paraganglioma inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MAX p.Ser45Asn (c.134G>A)?

AlphaMissense predicts ambiguous (score 0.4827) — an in-silico prediction, not a clinical call.

MAX p.Ser45Asn

c.134G>A · rs2139883912 · VCV1417350

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4827 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Conditions

hereditary pheochromocytoma-paraganglioma

Computational evidence

Protein change
AlphaMissense	0.4827	ambiguous
REVEL	0.469	indeterminate
SaProt	LLR -12.25	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 17 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,178,290 alleles

Overall 0.000124% 2/1,612,300 alleles · very rare exomes 2/1,459,966 · genomes 0/152,334 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,460
European (non-Finnish)grpmax	8.49e-05%	1,178,289

Remaining individuals 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: MAX
Protein: p.Ser45Asn
Coding: c.134G>A
MANE Select: NM_002382
dbSNP: rs2139883912
Type: single nucleotide variant
Location: chr14:65093745 (GRCh38)
Gene constraint: LOEUF 0.288 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 82.07 · 12 PDB
Residue 45: the bhlh domain; a UniProt-annotated variant site (in pcc; does not repress myc transcriptional activity); an α-helix

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

Disease context

hereditary pheochromocytoma-paraganglioma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Hereditary pheochromocytoma-paraganglioma (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

MAX p.Ser45Gly Uncertain significance ★★ ⚠ same residue
MAX c.295+1G>A Pathogenic ★★ same condition
MAX c.295+1G>T Pathogenic ★★ same condition
MAX p.Ala67Asp Pathogenic/Likely pathogenic ★★ same condition
MAX p.Arg33Ter Pathogenic ★★ same condition
MAX p.Arg75Ter Pathogenic ★★ same condition
MAX p.Gln19Ter Pathogenic/Likely pathogenic ★★ same condition
MAX p.Gln91Ter Pathogenic ★★ 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/max-p-ser45asn (accessed [today's date]).

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