Is SETD1B p.Ala1657= (c.4971G>A) pathogenic?

SETD1B p.Ala1657= (c.4971G>A) is classified Benign in SETD1B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-27). Common (popmax 56.4%, mid) — too common for a highly-penetrant pathogenic allele.

SETD1B p.Ala1657=

Q: How common is SETD1B p.Ala1657= (c.4971G>A) in the general population?

SETD1B p.Ala1657= (c.4971G>A) is common (popmax 56.4%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4971G>A · rs3741593 · VCV1284001

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 56.4%, mid) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.1	GERP -2.6
Overall
CADD	0.011	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 56.4% Middle Eastern · 3,381/5,992 alleles

Filtering AF 54.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 54.2%

Overall 51.3% 794,880/1,550,642 alleles · common exomes 733,166/1,398,800 · genomes 61,714/151,842 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	67.4%	1
Ashkenazi Jewishnot grpmax-eligible	61.7%	2
Middle Easterngrpmax	56.4%	2
East Asian	54.6%	2
European (non-Finnish)	54.3%	2
Remaining individualsnot grpmax-eligible	51.2%	2
South Asian	46.7%	2
Finnishnot grpmax-eligible	46.5%	2
Admixed American	46.3%	2
African / African-American	9.75%	10

Amish 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: SETD1B
Protein: p.Ala1657=
Coding: c.4971G>A
MANE Select: NM_001353345
dbSNP: rs3741593
Type: single nucleotide variant
Location: chr12:121823550 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 1657: the 'disordered' region; a UniProt-annotated variant site (in iddseld)

Full SETD1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SETD1B p.Ala1657Val Uncertain significance ★★ ⚠ same residue
SETD1B p.Arg1329Ter Pathogenic ★★ same type
SETD1B p.Arg1703Ter Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Arg1748Cys Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Arg1792Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
SETD1B p.Arg1825Trp Likely pathogenic ★★ same type
SETD1B p.Arg1902Cys Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Gln780Ter 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/setd1b-p-ala1657 (accessed [today's date]).

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