Is SETD5 p.Arg783Cys (c.2347C>T) pathogenic?

SETD5 p.Arg783Cys (c.2347C>T) is classified Uncertain significance in SETD5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-01). AlphaMissense: likely pathogenic (0.951); Very rare (popmax 0.00198%, amr); Associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency.

How common is SETD5 p.Arg783Cys (c.2347C>T) in the general population?

SETD5 p.Arg783Cys (c.2347C>T) is very rare (popmax 0.00198%, amr) (gnomAD).

What do computational predictors say about SETD5 p.Arg783Cys (c.2347C>T)?

AlphaMissense predicts likely pathogenic (score 0.951) — an in-silico prediction, not a clinical call.

SETD5 p.Arg783Cys

Q: What condition is associated with SETD5 p.Arg783Cys (c.2347C>T)?

SETD5 p.Arg783Cys (c.2347C>T) is associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (ClinVar).

c.2347C>T · rs752026901 · VCV2955873

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00198%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

Computational evidence

Protein change
AlphaMissense	0.951	likely pathogenic
REVEL	0.762	pathogenic-leaning
SaProt	LLR -9.94	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 26 kb · p 0.85 · 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 0.00198% Admixed American · 1/50,384 alleles

Filtering AF 0.000294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000212%

Overall 0.000568% 9/1,584,164 alleles · very rare exomes 7/1,432,102 · genomes 2/152,062 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00198%	50,384
European (non-Finnish)	0.000683%	146,453

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.Arg783Cys
Coding: c.2347C>T
MANE Select: NM_001080517
dbSNP: rs752026901
Type: single nucleotide variant
Location: chr3:9453739 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 783: a UniProt-annotated variant site (in mrd23)

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

Disease context

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD5 p.Arg783His Benign/Likely benign ★★ ⚠ same residue
SETD5 c.1441-1G>A Pathogenic ★★ same condition
SETD5 c.1525-1G>C Pathogenic/Likely pathogenic ★★ same condition
SETD5 c.2347-7A>G Pathogenic ★★ same condition
SETD5 c.3631+1G>A Pathogenic ★★ same condition
SETD5 c.960-5C>G Pathogenic/Likely pathogenic ★★ same condition
SETD5 p.Arg1001Ter Pathogenic ★★ same condition
SETD5 p.Arg1072Ter 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-arg783cys (accessed [today's date]).

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