Is MAP1B p.Met2446Val (c.7336A>G) pathogenic?

MAP1B p.Met2446Val (c.7336A>G) is classified Uncertain significance in MAP1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-04). AlphaMissense: likely pathogenic (0.6208); Ultra-rare (popmax 0.0164%, mid); Associated with hearing loss, autosomal dominant 83.

What condition is associated with MAP1B p.Met2446Val (c.7336A>G)?

MAP1B p.Met2446Val (c.7336A>G) is associated with hearing loss, autosomal dominant 83 (ClinVar).

How common is MAP1B p.Met2446Val (c.7336A>G) in the general population?

MAP1B p.Met2446Val (c.7336A>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about MAP1B p.Met2446Val (c.7336A>G)?

AlphaMissense predicts likely pathogenic (score 0.6208) — an in-silico prediction, not a clinical call.

MAP1B p.Met2446Val

c.7336A>G · rs1174484755 · VCV3067960

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6208 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hearing loss, autosomal dominant 83

Computational evidence

Protein change
AlphaMissense	0.6208	likely pathogenic
REVEL	0.386	indeterminate
SaProt	LLR -4.52	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.16, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 5,431 bp · p 1.1e-08 · regional, not allelic
Overall
CADD	22.3	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,613,888 alleles · ultra-rare exomes 8/1,461,768 · genomes 1/152,120 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.000678%	147,493

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.Met2446Val
Coding: c.7336A>G
MANE Select: NM_005909
dbSNP: rs1174484755
Type: single nucleotide variant
Location: chr5:72205168 (GRCh38)
Gene constraint: LOEUF 0.105 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 46.18
Residue 2446: a UniProt-annotated variant site (in pvnh9); a UniProt-annotated variant site (in pvnh9; no effect on protein expression); the 'mediates interaction with tmem185a' region

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

Disease context

hearing loss, autosomal dominant 83 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAP1B p.Met2446Thr Uncertain significance ★ ⚠ same residue
MAP1B p.Arg999Ter Pathogenic/Likely pathogenic ★★ same condition
MAP1B p.Arg1948Trp Uncertain significance ★★ ⚠ same condition
MAP1B p.Lys2253Arg Uncertain significance ★★ ⚠ same condition
MAP1B p.Val1549Gly Uncertain significance ★★ ⚠ same condition
MAP1B p.Pro1634= Benign/Likely benign ★★ same condition
MAP1B p.Ser1731= Benign/Likely benign ★★ same condition
MAP1B p.Ala273Val 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-met2446val (accessed [today's date]).

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