Is SIX5 p.Arg176= (c.528C>T) pathogenic?

SIX5 p.Arg176= (c.528C>T) is classified Likely benign in SIX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-17). Very rare (popmax 0.00416%, nfe).

How common is SIX5 p.Arg176= (c.528C>T) in the general population?

SIX5 p.Arg176= (c.528C>T) is very rare (popmax 0.00416%, nfe) (gnomAD).

SIX5 p.Arg176=

c.528C>T · rs758183735 · VCV2071310

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00416%, nfe)

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 1.4	GERP -3.3, phastCons 1
Overall
CADD	10.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00416% European (non-Finnish) · 49/1,177,928 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00287%

Overall 0.00323% 52/1,608,186 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00416%	24,039
Admixed American	0.00169%	59,338
Remaining individualsnot grpmax-eligible	0.00161%	62,204
African / African-American	0.00134%	74,868

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.Arg176=
Coding: c.528C>T
dbSNP: rs758183735
Type: single nucleotide variant
Location: chr19:45768317 (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-arg176 (accessed [today's date]).

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