Is SETD1A p.Arg375Cys (c.1123C>T) pathogenic?

SETD1A p.Arg375Cys (c.1123C>T) is classified Uncertain significance in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-05). AlphaMissense: ambiguous (0.4018); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with SETD1A p.Arg375Cys (c.1123C>T)?

SETD1A p.Arg375Cys (c.1123C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1A p.Arg375Cys (c.1123C>T) in the general population?

SETD1A p.Arg375Cys (c.1123C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about SETD1A p.Arg375Cys (c.1123C>T)?

AlphaMissense predicts ambiguous (score 0.4018) — an in-silico prediction, not a clinical call.

SETD1A p.Arg375Cys

c.1123C>T · rs780454569 · VCV3160572

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4018 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4018	ambiguous
REVEL	0.442	indeterminate
SaProt	LLR -9.12	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,694 bp · p 0.44 · regional, not allelic
Overall
CADD	28.9	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 0.00223% East Asian · 1/44,894 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00149% 24/1,614,090 alleles · very rare exomes 21/1,461,886 · genomes 3/152,204 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,894
European (non-Finnish)	0.00186%	53,638
African / African-American	0.00133%	74,930

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: SETD1A
Protein: p.Arg375Cys
Coding: c.1123C>T
MANE Select: NM_014712
dbSNP: rs780454569
Type: single nucleotide variant
Location: chr16:30964865 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 375: a UniProt-annotated variant site (in nedsid)

Full SETD1A 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

Similar variants

SETD1A p.Arg375Leu Uncertain significance ★ same residue
SETD1A p.Ala671Thr Uncertain significance ★★ ⚠ same condition
SETD1A p.Ala840Val Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg1576Trp Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg276Trp Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg385His Uncertain significance ★★ ⚠ same condition
SETD1A p.Cys1638Phe Uncertain significance ★★ ⚠ same condition
SETD1A p.Glu1009Lys Uncertain significance ★★ ⚠ 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/setd1a-p-arg375cys (accessed [today's date]).

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