Is SETD5 p.His43Arg (c.128A>G) pathogenic?

SETD5 p.His43Arg (c.128A>G) is classified Likely benign in SETD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-17). AlphaMissense: likely benign (0.3194); Ultra-rare (popmax 0.0111%, eas); Associated with Inborn genetic diseases.

What condition is associated with SETD5 p.His43Arg (c.128A>G)?

SETD5 p.His43Arg (c.128A>G) is associated with Inborn genetic diseases (ClinVar).

How common is SETD5 p.His43Arg (c.128A>G) in the general population?

SETD5 p.His43Arg (c.128A>G) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about SETD5 p.His43Arg (c.128A>G)?

AlphaMissense predicts likely benign (score 0.3194) — an in-silico prediction, not a clinical call.

SETD5 p.His43Arg

c.128A>G · rs765631607 · VCV2227714

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3194 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3194	likely benign
REVEL	0.306	indeterminate
SaProt	LLR -5.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.2	GERP 0.83, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 12 kb · p 2.7e-05 · regional, not allelic
Overall
CADD	22.3	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 0.0111% East Asian · 5/44,894 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000558% 9/1,613,872 alleles · ultra-rare exomes 8/1,461,664 · genomes 1/152,208 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,979
Finnishnot grpmax-eligible	0.00156%	64,008
European (non-Finnish)	0.000254%	393,292

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: SETD5
Protein: p.His43Arg
Coding: c.128A>G
MANE Select: NM_001080517
dbSNP: rs765631607
Type: single nucleotide variant
Location: chr3:9433901 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10

Full SETD5 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

SETD5 c.2347-7A>G Pathogenic ★★ same condition
SETD5 p.Arg1001Ter Pathogenic ★★ same condition
SETD5 p.Arg308Ter Pathogenic/Likely pathogenic ★★ same condition
SETD5 p.Arg361Ter Pathogenic ★★ same condition
SETD5 p.Gln1101Ter Pathogenic ★★ same condition
SETD5 p.Ser668Ter Pathogenic/Likely pathogenic ★★ same condition
SETD5 p.Ala1112Ser Uncertain significance ★★ ⚠ same condition
SETD5 p.Ala4Ser 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/setd5-p-his43arg (accessed [today's date]).

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