Is MAP4K2 p.Pro630Leu (c.1889C>T) pathogenic?

MAP4K2 p.Pro630Leu (c.1889C>T) is classified Uncertain significance in MAP4K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). AlphaMissense: likely pathogenic (0.8265); Rare (popmax 0.281%, mid).

How common is MAP4K2 p.Pro630Leu (c.1889C>T) in the general population?

MAP4K2 p.Pro630Leu (c.1889C>T) is rare (popmax 0.281%, mid) (gnomAD).

What do computational predictors say about MAP4K2 p.Pro630Leu (c.1889C>T)?

AlphaMissense predicts likely pathogenic (score 0.8265) — an in-silico prediction, not a clinical call.

MAP4K2 p.Pro630Leu

c.1889C>T · rs145848436 · VCV2457791

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8265 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.281%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8265	likely pathogenic
REVEL	0.457	indeterminate
SaProt	LLR -10.14	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.0094 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.281% Middle Eastern · 17/6,050 alleles

Filtering AF 0.179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.147%

Overall 0.0128% 207/1,611,876 alleles · rare exomes 184/1,459,690 · genomes 23/152,186 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.281%	356
Ashkenazi Jewishnot grpmax-eligible	0.254%	394
Remaining individualsnot grpmax-eligible	0.0321%	3,119
South Asian	0.00881%	11,355
European (non-Finnish)	0.00704%	14,211
African / African-American	0.00267%	37,453
Admixed American	0.00167%	59,918
Finnishnot grpmax-eligible	0.00159%	62,938

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.Pro630Leu
Coding: c.1889C>T
MANE Select: NM_004579
dbSNP: rs145848436
Type: single nucleotide variant
Location: chr11:64792197 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.32
Residue 630: the cnh domain

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-pro630leu (accessed [today's date]).

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