Is SIX5 p.Phe192= (c.576C>T) pathogenic?

SIX5 p.Phe192= (c.576C>T) is classified Likely benign in SIX5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-13). Rare (popmax 0.214%, mid).

How common is SIX5 p.Phe192= (c.576C>T) in the general population?

SIX5 p.Phe192= (c.576C>T) is rare (popmax 0.214%, mid) (gnomAD).

SIX5 p.Phe192=

c.576C>T · rs368106223 · VCV744309

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.214%, mid)

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 4.9	GERP -0.16, phastCons 1
Overall
CADD	12.29	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.214% Middle Eastern · 13/6,082 alleles

Filtering AF 0.126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.1%

Overall 0.00583% 94/1,612,698 alleles · rare exomes 89/1,460,442 · genomes 5/152,256 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.214%	468
Remaining individualsnot grpmax-eligible	0.016%	6,243
South Asian	0.0121%	8,270
European (non-Finnish)	0.005%	19,994
African / African-American	0.00133%	74,922

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.Phe192=
Coding: c.576C>T
MANE Select: NM_175875
dbSNP: rs368106223
Type: single nucleotide variant
Location: chr19:45768269 (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-phe192 (accessed [today's date]).

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