Is MAP1B p.Pro1966Thr (c.5896C>A) pathogenic?

MAP1B p.Pro1966Thr (c.5896C>A) is classified Uncertain significance in MAP1B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-06). AlphaMissense: likely benign (0.041); Very rare (popmax 0.00167%, amr); Associated with periventricular nodular heterotopia 9.

What condition is associated with MAP1B p.Pro1966Thr (c.5896C>A)?

MAP1B p.Pro1966Thr (c.5896C>A) is associated with periventricular nodular heterotopia 9 (ClinVar).

How common is MAP1B p.Pro1966Thr (c.5896C>A) in the general population?

MAP1B p.Pro1966Thr (c.5896C>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about MAP1B p.Pro1966Thr (c.5896C>A)?

AlphaMissense predicts likely benign (score 0.041) — an in-silico prediction, not a clinical call.

MAP1B p.Pro1966Thr

c.5896C>A · rs534481306 · VCV1704367

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.041 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

periventricular nodular heterotopia 9

Computational evidence

Protein change
AlphaMissense	0.041	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -2.34	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 4.5	GERP -0.31, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 5,330 bp · p 1.3e-05 · regional, not allelic
Overall
CADD	6.462	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 0.00167% Admixed American · 1/60,006 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,613,960 alleles · very rare exomes 3/1,461,868 · genomes 2/152,092 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,006
South Asian	0.0011%	91,062
European (non-Finnish)	0.000254%	393,331

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.Pro1966Thr
Coding: c.5896C>A
MANE Select: NM_005909
dbSNP: rs534481306
Type: single nucleotide variant
Location: chr5:72199251 (GRCh38)
Gene constraint: LOEUF 0.105 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 46.18
Residue 1966: a UniProt-annotated variant site (in pvnh9); a UniProt-annotated variant site (in pvnh9; no effect on protein expression); the 'disordered' region

Full MAP1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

periventricular nodular heterotopia 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAP1B p.Pro1966Ala Uncertain significance ★ ⚠ same residue
MAP1B p.Arg1664Ter Pathogenic/Likely pathogenic ★★ same condition
MAP1B p.Arg303Ter Pathogenic/Likely pathogenic ★★ same condition
MAP1B p.Arg85Ter Pathogenic/Likely pathogenic ★★ same condition
MAP1B p.Arg999Ter Pathogenic/Likely pathogenic ★★ same condition
MAP1B p.Arg1399Cys Uncertain significance ★★ ⚠ same condition
MAP1B p.Glu1944Lys Uncertain significance ★★ ⚠ same condition
MAP1B p.Leu1453Val 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/map1b-p-pro1966thr (accessed [today's date]).

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