Is SETD7 p.Cys303Ser (c.908G>C) pathogenic?

SETD7 p.Cys303Ser (c.908G>C) is classified Uncertain significance in SETD7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-09). AlphaMissense: ambiguous (0.4956); Very rare (popmax 0.00133%, afr).

How common is SETD7 p.Cys303Ser (c.908G>C) in the general population?

SETD7 p.Cys303Ser (c.908G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about SETD7 p.Cys303Ser (c.908G>C)?

AlphaMissense predicts ambiguous (score 0.4956) — an in-silico prediction, not a clinical call.

SETD7 p.Cys303Ser

c.908G>C · rs1727072447 · VCV3160694

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4956 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4956	ambiguous
REVEL	0.798	moderately pathogenic-leaning
SaProt	LLR -8.36	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 38 kb · p 1.1e-08 · regional, not allelic
Overall
CADD	25.3	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 0.00133% African / African-American · 1/75,012 alleles

Overall 6.2e-05% 1/1,613,126 alleles · very rare exomes 1/1,460,832 · genomes 0/152,294 · 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: SETD7
Protein: p.Cys303Ser
Coding: c.908G>C
MANE Select: NM_030648
dbSNP: rs1727072447
Type: single nucleotide variant
Location: chr4:139517897 (GRCh38)
Gene constraint: LOEUF 0.605 · pLI 0.65 (gnomAD)
Structure: AlphaFold pLDDT 94.51 · 32 PDB
Residue 303: the set domain; a β-strand

Full SETD7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SETD7 p.Pro22= Benign ★★ same type
SETD7 p.Arg115Cys Uncertain significance ★ ⚠ same type
SETD7 p.Arg179Thr Uncertain significance ★ ⚠ same type
SETD7 p.Asp101His Uncertain significance ★ ⚠ same type
SETD7 p.Asp306Asn Uncertain significance ★ ⚠ same type
SETD7 p.Cys288Ser Uncertain significance ★ ⚠ same type
SETD7 p.Cys288Tyr Uncertain significance ★ ⚠ same type
SETD7 p.Gly102Arg 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/setd7-p-cys303ser (accessed [today's date]).

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