Is SETD5 p.Ser1371Phe (c.4112C>T) pathogenic?

SETD5 p.Ser1371Phe (c.4112C>T) is classified Uncertain significance in SETD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-07). AlphaMissense: likely benign (0.2793); Very rare (popmax 0.004%, afr).

How common is SETD5 p.Ser1371Phe (c.4112C>T) in the general population?

SETD5 p.Ser1371Phe (c.4112C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about SETD5 p.Ser1371Phe (c.4112C>T)?

AlphaMissense predicts likely benign (score 0.2793) — an in-silico prediction, not a clinical call.

SETD5 p.Ser1371Phe

c.4112C>T · rs1238145433 · VCV1368518

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2793 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2793	likely benign
REVEL	0.332	indeterminate
SaProt	LLR -8.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
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	25.9	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 0.004% African / African-American · 3/74,936 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,906 alleles · very rare exomes 2/1,461,704 · genomes 1/152,202 · 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.Ser1371Phe
Coding: c.4112C>T
MANE Select: NM_001080517
dbSNP: rs1238145433
Type: single nucleotide variant
Location: chr3:9475874 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 1371: 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.Ser1371fs 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-ser1371phe (accessed [today's date]).

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