Is MAP1A p.Leu166Phe (c.498A>C) pathogenic?

MAP1A p.Leu166Phe (c.498A>C) is classified Uncertain significance in MAP1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-10). AlphaMissense: likely pathogenic (0.9428); Rare (popmax 0.197%, nfe).

How common is MAP1A p.Leu166Phe (c.498A>C) in the general population?

MAP1A p.Leu166Phe (c.498A>C) is rare (popmax 0.197%, nfe) (gnomAD).

What do computational predictors say about MAP1A p.Leu166Phe (c.498A>C)?

AlphaMissense predicts likely pathogenic (score 0.9428) — an in-silico prediction, not a clinical call.

MAP1A p.Leu166Phe

c.498A>C · rs2079321019 · VCV2230695

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9428 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.197%, nfe)

Computational evidence

Protein change
AlphaMissense	0.9428	likely pathogenic
REVEL	0.375	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.22	GERP -4, phastCons 0.27
Overall
CADD	17.48	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.197% European (non-Finnish) · 2,267/1,148,980 alleles

Filtering AF 0.191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.188%

Overall 0.157% 2,483/1,579,140 alleles · rare exomes 2,470/1,427,032 · genomes 13/152,108 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.197%	507
Remaining individualsnot grpmax-eligible	0.135%	738
African / African-American	0.0593%	1,687
South Asian	0.0553%	1,807
Middle Eastern	0.05%	2,000
Ashkenazi Jewishnot grpmax-eligible	0.0478%	2,093
East Asian	0.0292%	3,420
Finnishnot grpmax-eligible	0.011%	9,102
Admixed American	0.00334%	29,944

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: MAP1A
Protein: p.Leu166Phe
Coding: c.498A>C
MANE Select: NM_002373
dbSNP: rs2079321019
Type: single nucleotide variant
Location: chr15:43521971 (GRCh38)
Structure: AlphaFold pLDDT 94.44 · 41 PDB
Residue 166: an α-helix

Full MAP1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

METAP1 p.Ile166Val Uncertain significance ★ ⚠ same residue
MAP1A p.Arg2734Gln Uncertain significance ★★ same type
MAP1A p.Gly567Ala Uncertain significance ★★ ⚠ same type
MAP1A p.Gly482= Benign/Likely benign ★★ same type
MAP1A p.Leu1621Val Benign ★★ same type
MAP1A p.Ser1152= Likely benign ★★ same type
MAP1A p.Ser1311= Benign/Likely benign ★★ same type
MAP1A p.Ser1544= Benign ★★ same type

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/map1a-p-leu166phe (accessed [today's date]).

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