Is SETD2 p.Met1723Val (c.5167A>G) pathogenic?

SETD2 p.Met1723Val (c.5167A>G) is classified Uncertain significance in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-06). AlphaMissense: likely benign (0.1115); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with SETD2 p.Met1723Val (c.5167A>G)?

SETD2 p.Met1723Val (c.5167A>G) is associated with Inborn genetic diseases (ClinVar).

How common is SETD2 p.Met1723Val (c.5167A>G) in the general population?

SETD2 p.Met1723Val (c.5167A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about SETD2 p.Met1723Val (c.5167A>G)?

AlphaMissense predicts likely benign (score 0.1115) — an in-silico prediction, not a clinical call.

SETD2 p.Met1723Val

c.5167A>G · rs778443256 · VCV3160643

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1115 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1115	likely benign
REVEL	0.202	benign-leaning
SaProt	LLR -5.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.1	GERP -0.18, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 14 kb · p 1.7e-10 · regional, not allelic
Overall
CADD	21.7	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 0.00167% Admixed American · 1/59,954 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,613,460 alleles · very rare exomes 8/1,461,496 · genomes 0/151,964 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,954
European (non-Finnish)	0.000593%	168,539

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.Met1723Val
Coding: c.5167A>G
MANE Select: NM_014159
dbSNP: rs778443256
Type: single nucleotide variant
Location: chr3:47088223 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 1723: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a UniProt-annotated variant site (in all; uncertain significance; somatic mutation)

Full SETD2 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

SETD2 c.4715+5G>A Uncertain significance ★★ same condition
SETD2 p.Arg1197Thr Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg368Gln Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg540Gln Uncertain significance ★★ ⚠ same condition
SETD2 p.Asn1303Ser Uncertain significance ★★ ⚠ same condition
SETD2 p.Asn840Ser Uncertain significance ★★ ⚠ same condition
SETD2 p.Asp1169Gly Uncertain significance ★★ ⚠ same condition
SETD2 p.Asp294Val 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-met1723val (accessed [today's date]).

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