Is MAP4 p.Arg2081Cys (c.6241C>T) pathogenic?

MAP4 p.Arg2081Cys (c.6241C>T) is classified Uncertain significance in MAP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: ambiguous (0.5257); Very rare (popmax 0.00336%, amr).

How common is MAP4 p.Arg2081Cys (c.6241C>T) in the general population?

MAP4 p.Arg2081Cys (c.6241C>T) is very rare (popmax 0.00336%, amr) (gnomAD).

What do computational predictors say about MAP4 p.Arg2081Cys (c.6241C>T)?

AlphaMissense predicts ambiguous (score 0.5257) — an in-silico prediction, not a clinical call.

MAP4 p.Arg2081Cys

c.6241C>T · VCV4549556

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5257 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00336%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5257	ambiguous
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -11.71	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 23 kb · p 0.28 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R936C vs ClinVar R2081C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00336% Admixed American · 2/59,502 alleles

Filtering AF 0.000558% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000209%

Overall 0.000373% 6/1,606,796 alleles · very rare exomes 3/1,454,584 · genomes 3/152,212 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00336%	29,751
South Asian	0.00111%	90,166
European (non-Finnish)	0.000255%	391,802

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: MAP4
Protein: p.Arg2081Cys
Coding: c.6241C>T
MANE Select: NM_001385682
Type: single nucleotide variant
Location: chr3:47870866 (GRCh38)
Gene constraint: LOEUF 0.512 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 43.03
Residue 936 UniProt numbering: the 'disordered' region

Full MAP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP4 c.292+9T>G Benign ★★ same type
MAP4 p.Gln1950= Benign ★★ same type
MAP4 p.Leu516= Likely benign ★★ same type
MAP4 p.Val37= Benign ★★ same type
MAP4 p.Ala150Ser Uncertain significance ★ ⚠ same type
MAP4 p.Ala1922Val Uncertain significance ★ ⚠ same type
MAP4 p.Ala1926Pro Uncertain significance ★ ⚠ same type
MAP4 p.Ala1941Thr Uncertain significance ★ ⚠ 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/map4-p-arg2081cys (accessed [today's date]).

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