Is MAP1B p.Pro646Leu (c.1937C>T) pathogenic?

MAP1B p.Pro646Leu (c.1937C>T) is classified Uncertain significance in MAP1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-16). AlphaMissense: likely benign (0.0841); Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MAP1B p.Pro646Leu (c.1937C>T)?

MAP1B p.Pro646Leu (c.1937C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MAP1B p.Pro646Leu (c.1937C>T) in the general population?

MAP1B p.Pro646Leu (c.1937C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about MAP1B p.Pro646Leu (c.1937C>T)?

AlphaMissense predicts likely benign (score 0.0841) — an in-silico prediction, not a clinical call.

MAP1B p.Pro646Leu

c.1937C>T · VCV3292931

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0841 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0841	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -7.92	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 2.8	GERP 1.4, phastCons 0.036
Regional constraint	o/e 0.91	unconstrained · MANE · 5,330 bp · p 1.3e-05 · regional, not allelic
Overall
CADD	16.38	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 0.00017% European (non-Finnish) · 2/1,179,738 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,612,628 alleles · very rare exomes 2/1,461,456 · genomes 0/151,172 · 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: MAP1B
Protein: p.Pro646Leu
Coding: c.1937C>T
MANE Select: NM_005909
Type: single nucleotide variant
Location: chr5:72195292 (GRCh38)
Gene constraint: LOEUF 0.105 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 46.18
Residue 646: the 'disordered' region; a UniProt-annotated variant site (in pvnh9)

Full MAP1B 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

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MAP1B p.Glu1944Lys Uncertain significance ★★ ⚠ same condition
MAP1B p.Glu2435Val Uncertain significance ★★ ⚠ same condition
MAP1B p.Gly919Arg Uncertain significance ★★ ⚠ same condition
MAP1B p.Gly932Ser Uncertain significance ★★ ⚠ same condition
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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/map1b-p-pro646leu (accessed [today's date]).

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