Is MAP4K2 p.Pro653Ser (c.1957C>T) pathogenic?

MAP4K2 p.Pro653Ser (c.1957C>T) is classified Uncertain significance in MAP4K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-02). AlphaMissense: likely pathogenic (0.8123); Ultra-rare (popmax 0.0268%, afr).

How common is MAP4K2 p.Pro653Ser (c.1957C>T) in the general population?

MAP4K2 p.Pro653Ser (c.1957C>T) is ultra-rare (popmax 0.0268%, afr) (gnomAD).

What do computational predictors say about MAP4K2 p.Pro653Ser (c.1957C>T)?

AlphaMissense predicts likely pathogenic (score 0.8123) — an in-silico prediction, not a clinical call.

MAP4K2 p.Pro653Ser

c.1957C>T · rs373936475 · VCV2211001

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8123 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0268%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8123	likely pathogenic
REVEL	0.088	moderately benign-leaning
SaProt	LLR -9.44	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.0094 · regional, not allelic
Overall
CADD	23.9	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 0.0268% African / African-American · 20/74,644 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0148%

Overall 0.00201% 32/1,595,848 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0268%	3,732
Admixed American	0.00519%	19,275
European (non-Finnish)	0.000768%	130,183

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.Pro653Ser
Coding: c.1957C>T
MANE Select: NM_004579
dbSNP: rs373936475
Type: single nucleotide variant
Location: chr11:64792044 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.32
Residue 653: the cnh domain

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

Similar variants

MAP4K2 p.Pro653Gln Uncertain significance ★ ⚠ same residue
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

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-pro653ser (accessed [today's date]).

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