Is SIX5 p.Arg33= (c.99C>T) pathogenic?

SIX5 p.Arg33= (c.99C>T) is classified Likely benign in SIX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-09). Ultra-rare (popmax 0.0283%, amr).

How common is SIX5 p.Arg33= (c.99C>T) in the general population?

SIX5 p.Arg33= (c.99C>T) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

SIX5 p.Arg33=

c.99C>T · rs1331402977 · VCV723032

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4	GERP 0.38, phastCons 1
Overall
CADD	14.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0283% Admixed American · 14/49,504 alleles

Filtering AF 0.017% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00145% 22/1,518,488 alleles · ultra-rare exomes 12/1,367,220 · genomes 10/151,268 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0283%	3,536
European (non-Finnish)	0.000702%	142,430

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: SIX5
Protein: p.Arg33=
Coding: c.99C>T
MANE Select: NM_175875
dbSNP: rs1331402977
Type: single nucleotide variant
Location: chr19:45768746 (GRCh38)

Full SIX5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/six5-p-arg33 (accessed [today's date]).

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