Is SIX5 p.Thr82= (c.246G>A) pathogenic?

SIX5 p.Thr82= (c.246G>A) is classified Likely benign in SIX5 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-02-11). Ultra-rare (popmax 0.0281%, mid).

How common is SIX5 p.Thr82= (c.246G>A) in the general population?

SIX5 p.Thr82= (c.246G>A) is ultra-rare (popmax 0.0281%, mid) (gnomAD).

SIX5 p.Thr82=

c.246G>A · rs903299922 · VCV2890787

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0281%, 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 -0.16	GERP -1.6, phastCons 0.54
Overall
CADD	14.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0281% Middle Eastern · 1/3,554 alleles

Filtering AF 0.00204% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00127%

Overall 0.000679% 9/1,325,256 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0281%	3,554
African / African-American	0.00618%	16,186
Remaining individualsnot grpmax-eligible	0.00596%	16,791
European (non-Finnish)	9.55e-05%	1,046,752

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.Thr82=
Coding: c.246G>A
dbSNP: rs903299922
Type: single nucleotide variant
Location: chr19:45768599 (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-thr82 (accessed [today's date]).

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