Is SETD5 p.Pro1375Ser (c.4123C>T) pathogenic?

SETD5 p.Pro1375Ser (c.4123C>T) is classified Conflicting classifications of pathogenicity in SETD5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-01). AlphaMissense: likely benign (0.0804); Ultra-rare (popmax 0.0107%, afr).

How common is SETD5 p.Pro1375Ser (c.4123C>T) in the general population?

SETD5 p.Pro1375Ser (c.4123C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about SETD5 p.Pro1375Ser (c.4123C>T)?

AlphaMissense predicts likely benign (score 0.0804) — an in-silico prediction, not a clinical call.

SETD5 p.Pro1375Ser

c.4123C>T · rs756264715 · VCV1904968

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0804 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0804	likely benign
REVEL	0.234	benign-leaning
SaProt	LLR -5.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.1	GERP -1.3, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,020 bp · p 0.14 · regional, not allelic
Overall
CADD	17.84	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 0.0107% African / African-American · 8/74,926 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000496% 8/1,613,920 alleles · ultra-rare exomes 3/1,461,702 · genomes 5/152,218 · 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.Pro1375Ser
Coding: c.4123C>T
MANE Select: NM_001080517
dbSNP: rs756264715
Type: single nucleotide variant
Location: chr3:9475885 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 1375: 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.Pro1375fs Likely pathogenic ★ 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
SETD5 c.960-5C>G Pathogenic/Likely pathogenic ★★ same type
SETD5 p.Arg1001Ter 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-pro1375ser (accessed [today's date]).

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