Is SETD1A p.Arg115Cys (c.343C>T) pathogenic?

SETD1A p.Arg115Cys (c.343C>T) is classified Likely benign in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-01). AlphaMissense: likely benign (0.2845); Very rare (popmax 0.00754%, nfe).

How common is SETD1A p.Arg115Cys (c.343C>T) in the general population?

SETD1A p.Arg115Cys (c.343C>T) is very rare (popmax 0.00754%, nfe) (gnomAD).

What do computational predictors say about SETD1A p.Arg115Cys (c.343C>T)?

AlphaMissense predicts likely benign (score 0.2845) — an in-silico prediction, not a clinical call.

SETD1A p.Arg115Cys

c.343C>T · rs375220437 · VCV1694793

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2845 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00754%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2845	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 4,312 bp · p 8.3e-13 · regional, not allelic
Overall
CADD	34.0	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 0.00754% European (non-Finnish) · 89/1,180,038 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00601% 97/1,614,054 alleles · very rare exomes 90/1,461,886 · genomes 7/152,168 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00754%	13,259
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
African / African-American	0.00267%	37,450
Admixed American	0.00167%	60,002
South Asian	0.0011%	91,090

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.Arg115Cys
Coding: c.343C>T
MANE Select: NM_014712
dbSNP: rs375220437
Type: single nucleotide variant
Location: chr16:30961363 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 115: the rrm domain; a UniProt-annotated variant site (in nedsid); a turn

Full SETD1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SETD1A c.518-2A>G Pathogenic ★★ same type
SETD1A p.Arg1571Ter Pathogenic/Likely pathogenic ★★ same type
SETD1A p.Arg176Ter Pathogenic/Likely pathogenic ★★ same type
SETD1A p.Arg668Ter Pathogenic ★★ same type
SETD1A p.Arg913Cys Likely pathogenic ★★ ⚠ same type
SETD1A p.Arg990Ter Pathogenic/Likely pathogenic ★★ same type
SETD1A p.Tyr646Ter Pathogenic ★★ same type
SETD1A c.4692+3G>A Uncertain significance ★★ 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/setd1a-p-arg115cys (accessed [today's date]).

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