Is SETD5 p.Arg1387Trp (c.4159C>T) pathogenic?

SETD5 p.Arg1387Trp (c.4159C>T) is classified Uncertain significance in SETD5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-04-01). AlphaMissense: ambiguous (0.3743); Very rare (popmax 0.008%, afr); Associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency.

How common is SETD5 p.Arg1387Trp (c.4159C>T) in the general population?

SETD5 p.Arg1387Trp (c.4159C>T) is very rare (popmax 0.008%, afr) (gnomAD).

What do computational predictors say about SETD5 p.Arg1387Trp (c.4159C>T)?

AlphaMissense predicts ambiguous (score 0.3743) — an in-silico prediction, not a clinical call.

SETD5 p.Arg1387Trp

Q: What condition is associated with SETD5 p.Arg1387Trp (c.4159C>T)?

SETD5 p.Arg1387Trp (c.4159C>T) is associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (ClinVar).

c.4159C>T · rs560529972 · VCV1176144

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3743 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.008%, afr)

Conditions

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

Computational evidence

Protein change
AlphaMissense	0.3743	ambiguous
REVEL	0.506	indeterminate
SaProt	LLR -8.99	tolerated
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	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 0.008% African / African-American · 6/75,046 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.00173% 28/1,614,048 alleles · very rare exomes 23/1,461,710 · genomes 5/152,338 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.008%	12,508
European (non-Finnish)	0.00178%	56,186
Admixed American	0.00167%	60,032

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.Arg1387Trp
Coding: c.4159C>T
MANE Select: NM_001080517
dbSNP: rs560529972
Type: single nucleotide variant
Location: chr3:9475921 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 1387: 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 p.Arg1387Gly Uncertain significance ★ same residue
SETD5 p.Arg1387Gln 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

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-arg1387trp (accessed [today's date]).

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