Is MAX p.Pro16Leu (c.47C>T) pathogenic?

MAX p.Pro16Leu (c.47C>T) is classified Uncertain significance in MAX (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-13). AlphaMissense: likely benign (0.1875); Very rare (popmax 0.00034%, nfe); Associated with pheochromocytoma.

What condition is associated with MAX p.Pro16Leu (c.47C>T)?

MAX p.Pro16Leu (c.47C>T) is associated with pheochromocytoma, hereditary neoplastic syndrome, hereditary pheochromocytoma-paraganglioma (ClinVar).

How common is MAX p.Pro16Leu (c.47C>T) in the general population?

MAX p.Pro16Leu (c.47C>T) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about MAX p.Pro16Leu (c.47C>T)?

AlphaMissense predicts likely benign (score 0.1875) — an in-silico prediction, not a clinical call.

MAX p.Pro16Leu

c.47C>T · rs2063834899 · VCV1006095

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1875 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pheochromocytoma

Computational evidence

Protein change
AlphaMissense	0.1875	likely benign
REVEL	0.475	indeterminate
SaProt	LLR -11.31	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 8,551 bp · p 0.0042 · regional, not allelic
Overall
CADD	26.5	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 0.00034% European (non-Finnish) · 4/1,176,206 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000275% 4/1,457,038 alleles · very rare

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.Pro16Leu
Coding: c.47C>T
MANE Select: NM_002382
dbSNP: rs2063834899
Type: single nucleotide variant
Location: chr14:65101562 (GRCh38)
Gene constraint: LOEUF 0.288 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 82.07 · 12 PDB
Residue 16: the 'disordered' region

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

Disease context

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

Also linked: hereditary neoplastic syndrome hereditary pheochromocytoma-paraganglioma

Similar variants

MAX p.Pro16Ala Uncertain significance ★★ ⚠ same residue
MAX p.Pro16Thr Uncertain significance ★★ ⚠ same residue
MAX p.Pro16= Likely benign ★ 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

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-pro16leu (accessed [today's date]).

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