Is SETD7 p.His23Gln (c.69C>A) pathogenic?

SETD7 p.His23Gln (c.69C>A) is classified Uncertain significance in SETD7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely pathogenic (0.6045); Very rare (popmax 0.000593%, nfe).

How common is SETD7 p.His23Gln (c.69C>A) in the general population?

SETD7 p.His23Gln (c.69C>A) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about SETD7 p.His23Gln (c.69C>A)?

AlphaMissense predicts likely pathogenic (score 0.6045) — an in-silico prediction, not a clinical call.

SETD7 p.His23Gln

c.69C>A · VCV3952890

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6045 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6045	likely pathogenic
REVEL	0.46	indeterminate
SaProt	LLR -10.50	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -3.7
Regional constraint	o/e 0.71	unconstrained · MANE · 38 kb · p 1.1e-08 · regional, not allelic
Overall
CADD	19.4	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 0.000593% European (non-Finnish) · 7/1,180,006 alleles

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

Overall 0.000434% 7/1,614,088 alleles · very rare exomes 7/1,461,874 · genomes 0/152,214 · 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: SETD7
Protein: p.His23Gln
Coding: c.69C>A
MANE Select: NM_030648
Type: single nucleotide variant
Location: chr4:139547021 (GRCh38)
Gene constraint: LOEUF 0.605 · pLI 0.65 (gnomAD)
Structure: AlphaFold pLDDT 94.51 · 32 PDB

Full SETD7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SETD7 p.His23Arg Uncertain significance ★ ⚠ same residue
SETD7 p.Pro22= Benign ★★ same type
SETD7 p.Arg115Cys Uncertain significance ★ ⚠ same type
SETD7 p.Arg179Thr Uncertain significance ★ ⚠ same type
SETD7 p.Asp101His Uncertain significance ★ ⚠ same type
SETD7 p.Asp306Asn Uncertain significance ★ ⚠ same type
SETD7 p.Cys288Ser Uncertain significance ★ ⚠ same type
SETD7 p.Cys288Tyr 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/setd7-p-his23gln (accessed [today's date]).

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