Is SETD2 p.Lys145Asn (c.435G>C) pathogenic?

SETD2 p.Lys145Asn (c.435G>C) is classified Uncertain significance in SETD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-14). AlphaMissense: likely pathogenic (0.997); Very rare (popmax 0.000959%, nfe); Associated with intellectual developmental disorder, autosomal dominant 70.

What condition is associated with SETD2 p.Lys145Asn (c.435G>C)?

SETD2 p.Lys145Asn (c.435G>C) is associated with intellectual developmental disorder, autosomal dominant 70 (ClinVar).

How common is SETD2 p.Lys145Asn (c.435G>C) in the general population?

SETD2 p.Lys145Asn (c.435G>C) is very rare (popmax 0.000959%, nfe) (gnomAD).

What do computational predictors say about SETD2 p.Lys145Asn (c.435G>C)?

AlphaMissense predicts likely pathogenic (score 0.997) — an in-silico prediction, not a clinical call.

SETD2 p.Lys145Asn

c.435G>C · rs749274416 · VCV1334579

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.997 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000959%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual developmental disorder, autosomal dominant 70

Computational evidence

Protein change
AlphaMissense	0.997	likely pathogenic · top 4% in SETD2
REVEL	0.443	indeterminate
SaProt	LLR -6.83	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 0.54, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 40 kb · p 0.036 · regional, not allelic
Overall
CADD	21.9	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 0.000959% European (non-Finnish) · 11/1,147,022 alleles

Filtering AF 0.000515% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000376%

Overall 0.000709% 11/1,551,710 alleles · very rare exomes 10/1,399,498 · genomes 1/152,212 · 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: SETD2
Protein: p.Lys145Asn
Coding: c.435G>C
MANE Select: NM_014159
dbSNP: rs749274416
Type: single nucleotide variant
Location: chr3:47124201 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 145: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation)

Full SETD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual developmental disorder, autosomal dominant 70 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD2 p.Arg1740Gln Pathogenic ★★ ⚠ same condition
SETD2 p.Arg1740Trp Pathogenic/Likely pathogenic ★★ same condition
SETD2 p.Arg401Gln Uncertain significance ★★ ⚠ same condition
SETD2 p.His266Tyr Uncertain significance ★★ ⚠ same condition
SETD2 p.Ser1207= Likely benign ★★ same condition
SETD2 p.Val1743Leu Likely pathogenic ★ ⚠ same condition
SETD2 c.4840-1G>A Uncertain significance ★ same condition
SETD2 p.Arg1790Gln Uncertain significance ★ ⚠ 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/setd2-p-lys145asn (accessed [today's date]).

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