Is MAP4K4 p.Pro334Ser (c.1000C>T) pathogenic?

MAP4K4 p.Pro334Ser (c.1000C>T) is classified Uncertain significance in MAP4K4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-28). AlphaMissense: likely benign (0.0881); Very rare (popmax 0.00467%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MAP4K4 p.Pro334Ser (c.1000C>T)?

MAP4K4 p.Pro334Ser (c.1000C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MAP4K4 p.Pro334Ser (c.1000C>T) in the general population?

MAP4K4 p.Pro334Ser (c.1000C>T) is very rare (popmax 0.00467%, nfe) (gnomAD).

What do computational predictors say about MAP4K4 p.Pro334Ser (c.1000C>T)?

AlphaMissense predicts likely benign (score 0.0881) — an in-silico prediction, not a clinical call.

MAP4K4 p.Pro334Ser

c.1000C>T · rs759833561 · VCV2541682

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0881 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00467%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0881	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -7.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 158 kb · p 1.1e-42 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00467% European (non-Finnish) · 55/1,177,146 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0033%

Overall 0.00342% 55/1,608,260 alleles · very rare exomes 52/1,456,126 · genomes 3/152,134 · joint denominator

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: MAP4K4
Protein: p.Pro334Ser
Coding: c.1000C>T
MANE Select: NM_001395002
dbSNP: rs759833561
Type: single nucleotide variant
Location: chr2:101842659 (GRCh38)
Gene constraint: LOEUF 0.308 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.47 · 19 PDB
Residue 334: the 'disordered' region

Full MAP4K4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAP4K4 p.Arg1329Ter Pathogenic/Likely pathogenic ★★ same condition
MAP4K4 p.Ala491Pro Uncertain significance ★★ ⚠ same condition
MAP4K4 p.Leu742Pro Uncertain significance ★★ ⚠ same condition
MAP4K4 p.Ser758Phe Uncertain significance ★★ ⚠ same condition
MAP4K4 p.Asp203Gly Likely pathogenic ★ same condition
MAP4K4 p.Gln402Ter Pathogenic ★ same condition
MAP4K4 p.Gly173Asp Pathogenic ★ same condition
MAP4K4 p.Lys54Arg Likely pathogenic ★ same condition

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/map4k4-p-pro334ser (accessed [today's date]).

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