Is SETD5 p.Arg180His (c.539G>A) pathogenic?

SETD5 p.Arg180His (c.539G>A) is classified Likely benign in SETD5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-23). AlphaMissense: likely benign (0.195); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with SETD5 p.Arg180His (c.539G>A)?

SETD5 p.Arg180His (c.539G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SETD5 p.Arg180His (c.539G>A) in the general population?

SETD5 p.Arg180His (c.539G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about SETD5 p.Arg180His (c.539G>A)?

AlphaMissense predicts likely benign (score 0.195) — an in-silico prediction, not a clinical call.

SETD5 p.Arg180His

c.539G>A · rs756805346 · VCV2731179

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.195 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.195	likely benign
REVEL	0.486	indeterminate
SaProt	LLR -7.48	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 12 kb · p 2.7e-05 · regional, not allelic
Overall
CADD	31.0	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 0.0165% Middle Eastern · 1/6,056 alleles

Filtering AF 0.0025% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00219%

Overall 0.00276% 44/1,592,706 alleles · ultra-rare exomes 41/1,440,594 · genomes 3/152,112 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
Admixed American	0.00356%	28,112
European (non-Finnish)	0.00333%	29,991
East Asian	0.00227%	44,076
Remaining individualsnot grpmax-eligible	0.00162%	61,788

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.Arg180His
Coding: c.539G>A
MANE Select: NM_001080517
dbSNP: rs756805346
Type: single nucleotide variant
Location: chr3:9435878 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 180: the 'disordered' region

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 p.Arg180Cys Uncertain significance ★★ ⚠ same residue
SETD5 p.Arg180Leu Uncertain significance ★ same residue
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

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-arg180his (accessed [today's date]).

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