Is SIX5 p.Pro88= (c.264C>G) pathogenic?

SIX5 p.Pro88= (c.264C>G) is classified Likely benign in SIX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-24). Ultra-rare (popmax 0.0273%, mid).

How common is SIX5 p.Pro88= (c.264C>G) in the general population?

SIX5 p.Pro88= (c.264C>G) is ultra-rare (popmax 0.0273%, mid) (gnomAD).

SIX5 p.Pro88=

c.264C>G · rs1229444382 · VCV2183158

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0273%, mid)

⚠ 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 -2.1	GERP -3.8
Overall
CADD	2.875	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0273% Middle Eastern · 1/3,660 alleles

Overall 0.000147% 2/1,361,662 alleles · ultra-rare exomes 2/1,209,594 · genomes 0/152,068 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0273%	3,660
European (non-Finnish)	9.38e-05%	1,066,190

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.Pro88=
Coding: c.264C>G
MANE Select: NM_175875
dbSNP: rs1229444382
Type: single nucleotide variant
Location: chr19:45768581 (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-pro88 (accessed [today's date]).

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