Is SIX5 p.Pro226= (c.678C>G) pathogenic?

SIX5 p.Pro226= (c.678C>G) is classified Likely benign in SIX5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-28). Very rare (popmax 0.00667%, amr).

How common is SIX5 p.Pro226= (c.678C>G) in the general population?

SIX5 p.Pro226= (c.678C>G) is very rare (popmax 0.00667%, amr) (gnomAD).

SIX5 p.Pro226=

c.678C>G · VCV3708874

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00667%, 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 -1.7	GERP -4.3
Overall
CADD	8.219	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,956 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00031% 5/1,612,522 alleles · very rare exomes 3/1,460,264 · genomes 2/152,258 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,989
Remaining individualsnot grpmax-eligible	0.0016%	62,422

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.Pro226=
Coding: c.678C>G
MANE Select: NM_175875
Type: single nucleotide variant
Location: chr19:45768167 (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-pro226 (accessed [today's date]).

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