Is SETD5 p.Arg77His (c.230G>A) pathogenic?

SETD5 p.Arg77His (c.230G>A) is classified Benign in SETD5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.1105); Low-frequency (popmax 1.98%, afr).

How common is SETD5 p.Arg77His (c.230G>A) in the general population?

SETD5 p.Arg77His (c.230G>A) is low-frequency (popmax 1.98%, afr) (gnomAD).

What do computational predictors say about SETD5 p.Arg77His (c.230G>A)?

AlphaMissense predicts likely benign (score 0.1105) — an in-silico prediction, not a clinical call.

SETD5 p.Arg77His

c.230G>A · rs41387348 · VCV780373

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1105 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.98%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1105	likely benign
REVEL	0.351	indeterminate
SaProt	LLR -6.84	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 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 12 kb · p 2.7e-05 · regional, not allelic
Overall
CADD	27.1	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 1.98% African / African-American · 1,483/75,010 alleles

Filtering AF 1.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.86%

Overall 0.101% 1,629/1,613,902 alleles · low-frequency exomes 810/1,461,690 · genomes 819/152,212 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.98%	51
Remaining individualsnot grpmax-eligible	0.136%	735
Middle Eastern	0.0825%	1,212
Admixed American	0.075%	1,334
South Asian	0.00439%	22,769
European (non-Finnish)	0.000593%	168,553

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.Arg77His
Coding: c.230G>A
MANE Select: NM_001080517
dbSNP: rs41387348
Type: single nucleotide variant
Location: chr3:9434386 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 77: a UniProt-annotated variant site (in)

Full SETD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SETD5 p.Arg77Leu Uncertain significance ★ ⚠ same residue
SETD5 p.Arg77Ser Uncertain significance ★ ⚠ same residue
SETD5 c.1441-1G>A Pathogenic ★★ same type
SETD5 c.1525-1G>C Pathogenic/Likely pathogenic ★★ same type
SETD5 c.2347-1G>A Pathogenic ★★ same type
SETD5 c.2347-7A>G Pathogenic ★★ same type
SETD5 c.3631+1G>A Pathogenic ★★ same type
SETD5 c.960-5C>G Pathogenic/Likely pathogenic ★★ 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/setd5-p-arg77his (accessed [today's date]).

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