Is SETD5 p.Pro1318Arg (c.3953C>G) pathogenic?

SETD5 p.Pro1318Arg (c.3953C>G) is classified Uncertain significance in SETD5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-16). AlphaMissense: likely benign (0.205); Very rare (popmax 8.48e-05%, nfe); Associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency.

How common is SETD5 p.Pro1318Arg (c.3953C>G) in the general population?

SETD5 p.Pro1318Arg (c.3953C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SETD5 p.Pro1318Arg (c.3953C>G)?

AlphaMissense predicts likely benign (score 0.205) — an in-silico prediction, not a clinical call.

SETD5 p.Pro1318Arg

Q: What condition is associated with SETD5 p.Pro1318Arg (c.3953C>G)?

SETD5 p.Pro1318Arg (c.3953C>G) is associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (ClinVar).

c.3953C>G · rs2045789807 · VCV1513005

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.205 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

Computational evidence

Protein change
AlphaMissense	0.205	likely benign
REVEL	0.321	indeterminate
SaProt	LLR -6.90	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 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,020 bp · p 0.14 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,874 alleles

Overall 6.2e-05% 1/1,613,950 alleles · very rare exomes 1/1,461,666 · genomes 0/152,284 · joint denominator

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.Pro1318Arg
Coding: c.3953C>G
MANE Select: NM_001080517
dbSNP: rs2045789807
Type: single nucleotide variant
Location: chr3:9475715 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 1318: a UniProt-annotated variant site (in mrd23); the 'disordered' region

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 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
SETD5 p.Arg1121Ter 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-pro1318arg (accessed [today's date]).

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