Is SETD5 p.Pro1285= (c.3855C>G) pathogenic?

SETD5 p.Pro1285= (c.3855C>G) is classified Likely benign in SETD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). Ultra-rare (popmax 0.0164%, mid).

How common is SETD5 p.Pro1285= (c.3855C>G) in the general population?

SETD5 p.Pro1285= (c.3855C>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

SETD5 p.Pro1285=

c.3855C>G · VCV3608795

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.29	GERP -2.4, phastCons 0.2
Overall
CADD	5.524	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000806% 13/1,613,868 alleles · ultra-rare exomes 9/1,461,712 · genomes 4/152,156 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00534%	18,728
Admixed American	0.00333%	30,003
Remaining individualsnot grpmax-eligible	0.0032%	31,233
South Asian	0.0011%	91,084
European (non-Finnish)	0.000254%	393,300

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.Pro1285=
Coding: c.3855C>G
MANE Select: NM_001080517
Type: single nucleotide variant
Location: chr3:9475617 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 1285: a UniProt-annotated variant site (in mrd23); the 'disordered' region

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

Similar variants

SETD5 p.Pro1285Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
SETD5 p.Pro1285His Uncertain significance ★ ⚠ same residue
SETD5 p.Pro1285Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
SETD5 c.1441-1G>A Pathogenic ★★ same type
SETD5 c.1525-1G>C Pathogenic/Likely pathogenic ★★ same type
SETD5 c.2347-1G>A Pathogenic ★★ same type
SETD5 c.2347-7A>G Pathogenic ★★ same type
SETD5 c.3631+1G>A Pathogenic ★★ same type

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-pro1285 (accessed [today's date]).

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