Is SETD5 p.Arg64Cys (c.190C>T) pathogenic?

SETD5 p.Arg64Cys (c.190C>T) is classified Uncertain significance in SETD5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-15). AlphaMissense: ambiguous (0.5042); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with SETD5 p.Arg64Cys (c.190C>T)?

SETD5 p.Arg64Cys (c.190C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETD5 p.Arg64Cys (c.190C>T) in the general population?

SETD5 p.Arg64Cys (c.190C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about SETD5 p.Arg64Cys (c.190C>T)?

AlphaMissense predicts ambiguous (score 0.5042) — an in-silico prediction, not a clinical call.

SETD5 p.Arg64Cys

c.190C>T · rs995856475 · VCV2280685

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5042 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5042	ambiguous
REVEL	0.423	indeterminate
SaProt	LLR -6.89	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 12 kb · p 2.7e-05 · regional, not allelic
Overall
CADD	34.0	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 0.0011% South Asian · 1/91,072 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00062% 10/1,613,650 alleles · very rare exomes 9/1,461,484 · genomes 1/152,166 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,072
European (non-Finnish)	0.000763%	131,077

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.Arg64Cys
Coding: c.190C>T
MANE Select: NM_001080517
dbSNP: rs995856475
Type: single nucleotide variant
Location: chr3:9434346 (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 p.Arg64Gly Uncertain significance ★★ ⚠ same residue
SETD5 p.Arg64His Likely benign ★★ same residue
SETD5 p.Arg64Pro Benign/Likely benign ★★ ⚠ 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

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-arg64cys (accessed [today's date]).

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