Is SETD5 p.Ser960Gly (c.2878A>G) pathogenic?

SETD5 p.Ser960Gly (c.2878A>G) is classified Uncertain significance in SETD5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-02). AlphaMissense: likely benign (0.0554); Very rare (popmax 0.00669%, eas); Associated with Inborn genetic diseases.

What condition is associated with SETD5 p.Ser960Gly (c.2878A>G)?

SETD5 p.Ser960Gly (c.2878A>G) is associated with Inborn genetic diseases, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (ClinVar).

How common is SETD5 p.Ser960Gly (c.2878A>G) in the general population?

SETD5 p.Ser960Gly (c.2878A>G) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about SETD5 p.Ser960Gly (c.2878A>G)?

AlphaMissense predicts likely benign (score 0.0554) — an in-silico prediction, not a clinical call.

SETD5 p.Ser960Gly

c.2878A>G · rs2045194222 · VCV1353131

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0554 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0554	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -6.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 26 kb · p 0.85 · regional, not allelic
Overall
CADD	18.53	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 0.00669% East Asian · 3/44,874 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00112% 18/1,613,980 alleles · very rare exomes 18/1,461,710 · genomes 0/152,270 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,958
African / African-American	0.00133%	75,020
European (non-Finnish)	0.00119%	84,277

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.Ser960Gly
Coding: c.2878A>G
MANE Select: NM_001080517
dbSNP: rs2045194222
Type: single nucleotide variant
Location: chr3:9470612 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 960: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

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-ser960gly (accessed [today's date]).

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