Is SETD5 p.Arg769Ser (c.2307G>T) pathogenic?

SETD5 p.Arg769Ser (c.2307G>T) is classified Benign/Likely benign in SETD5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-01). AlphaMissense: likely pathogenic (0.7961); Ultra-rare (popmax 0.0598%, nfe).

How common is SETD5 p.Arg769Ser (c.2307G>T) in the general population?

SETD5 p.Arg769Ser (c.2307G>T) is ultra-rare (popmax 0.0598%, nfe) (gnomAD).

What do computational predictors say about SETD5 p.Arg769Ser (c.2307G>T)?

AlphaMissense predicts likely pathogenic (score 0.7961) — an in-silico prediction, not a clinical call.

SETD5 p.Arg769Ser

c.2307G>T · rs200540210 · VCV1201504

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7961 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0598%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7961	likely pathogenic
REVEL	0.705	pathogenic-leaning
SaProt	LLR -5.53	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 2	GERP 0.083, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 26 kb · p 0.85 · regional, not allelic
Overall
CADD	23.3	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 0.0598% European (non-Finnish) · 703/1,174,966 alleles

Filtering AF 0.0562% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0546%

Overall 0.0477% 766/1,606,334 alleles · ultra-rare exomes 723/1,454,254 · genomes 43/152,080 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0853%	1,173
European (non-Finnish)grpmax	0.0598%	1,671
Admixed American	0.0101%	9,921
African / African-American	0.00535%	18,694

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg769Ser
Coding: c.2307G>T
MANE Select: NM_001080517
dbSNP: rs200540210
Type: single nucleotide variant
Location: chr3:9448591 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 769: a UniProt-annotated variant site (in mrd23)

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

Similar variants

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
SETD5 c.960-5C>G Pathogenic/Likely pathogenic ★★ same type
SETD5 p.Arg1001Ter Pathogenic ★★ same type
SETD5 p.Arg1072Ter Pathogenic/Likely 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-arg769ser (accessed [today's date]).

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