Is SIX5 p.Leu165= (c.493C>T) pathogenic?

SIX5 p.Leu165= (c.493C>T) is classified Benign/Likely benign in SIX5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-12). Rare (popmax 0.231%, amr).

How common is SIX5 p.Leu165= (c.493C>T) in the general population?

SIX5 p.Leu165= (c.493C>T) is rare (popmax 0.231%, amr) (gnomAD).

SIX5 p.Leu165=

c.493C>T · rs368485758 · VCV681903

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.231%, 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 1.8	GERP -4.1, phastCons 1
Overall
CADD	12.04	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.231% Admixed American · 135/58,448 alleles

Filtering AF 0.199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.187%

Overall 0.0388% 621/1,599,390 alleles · rare exomes 496/1,447,084 · genomes 125/152,306 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.231%	433
Middle Eastern	0.116%	861
South Asian	0.11%	907
African / African-American	0.0387%	2,583
Remaining individualsnot grpmax-eligible	0.0291%	3,438
East Asian	0.027%	3,702
European (non-Finnish)	0.027%	3,707
Finnishnot grpmax-eligible	0.00681%	14,691

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.Leu165=
Coding: c.493C>T
MANE Select: NM_175875
dbSNP: rs368485758
Type: single nucleotide variant
Location: chr19:45768352 (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-leu165 (accessed [today's date]).

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