Is SIX5 p.Glu26= (c.78A>G) pathogenic?

SIX5 p.Glu26= (c.78A>G) is classified Likely benign in SIX5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-31). Ultra-rare (popmax 0.029%, nfe).

How common is SIX5 p.Glu26= (c.78A>G) in the general population?

SIX5 p.Glu26= (c.78A>G) is ultra-rare (popmax 0.029%, nfe) (gnomAD).

SIX5 p.Glu26=

c.78A>G · rs941642543 · VCV1317703

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, 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 -2.1	GERP -1.6
Overall
CADD	9.641	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.029% European (non-Finnish) · 331/1,143,052 alleles

Filtering AF 0.0264% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0253%

Overall 0.0236% 361/1,526,540 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.029%	3,453
Finnishnot grpmax-eligible	0.0251%	3,978
Remaining individualsnot grpmax-eligible	0.0168%	5,950
Admixed American	0.0119%	8,390
African / African-American	0.00415%	24,079

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.Glu26=
Coding: c.78A>G
dbSNP: rs941642543
Type: single nucleotide variant
Location: chr19:45768767 (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-glu26 (accessed [today's date]).

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