Is MAP4K2 p.Tyr820Cys (c.2459A>G) pathogenic?

MAP4K2 p.Tyr820Cys (c.2459A>G) is classified Uncertain significance in MAP4K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: ambiguous (0.37); Very rare (popmax 0.00403%, afr).

How common is MAP4K2 p.Tyr820Cys (c.2459A>G) in the general population?

MAP4K2 p.Tyr820Cys (c.2459A>G) is very rare (popmax 0.00403%, afr) (gnomAD).

What do computational predictors say about MAP4K2 p.Tyr820Cys (c.2459A>G)?

AlphaMissense predicts ambiguous (score 0.37) — an in-silico prediction, not a clinical call.

MAP4K2 p.Tyr820Cys

c.2459A>G · VCV4051443

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.37 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00403%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.37	ambiguous
REVEL	0.803	moderately pathogenic-leaning
SaProt	LLR -10.02	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 897 bp · p 5e-06 · regional, not allelic
Overall
CADD	25.1	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 0.00403% African / African-American · 3/74,440 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000497%

Overall 0.000253% 4/1,581,152 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00403%	24,813
South Asian	0.00115%	86,694

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: MAP4K2
Protein: p.Tyr820Cys
Coding: c.2459A>G
MANE Select: NM_004579
Type: single nucleotide variant
Location: chr11:64789541 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.32

Full MAP4K2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP4K2 p.Ala120Ser Benign ★★ same type
MAP4K2 p.Asn606= Benign ★★ same type
MAP4K2 p.Ala183Asp Uncertain significance ★ ⚠ same type
MAP4K2 p.Ala184Ser Uncertain significance ★ ⚠ same type
MAP4K2 p.Ala405Thr Uncertain significance ★ ⚠ same type
MAP4K2 p.Ala487Thr Uncertain significance ★ ⚠ same type
MAP4K2 p.Ala790Asp Uncertain significance ★ ⚠ same type
MAP4K2 p.Ala806Val 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/map4k2-p-tyr820cys (accessed [today's date]).

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