Is SIX5 p.Val573= (c.1719C>T) pathogenic?

SIX5 p.Val573= (c.1719C>T) is classified Likely benign in SIX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). Very rare (popmax 0.00224%, eas).

How common is SIX5 p.Val573= (c.1719C>T) in the general population?

SIX5 p.Val573= (c.1719C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

SIX5 p.Val573=

c.1719C>T · VCV3608204

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 0.38, phastCons 1
Overall
CADD	8.617	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% East Asian · 1/44,718 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000623% 10/1,605,374 alleles · very rare exomes 8/1,453,200 · genomes 2/152,174 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,718
Admixed American	0.00169%	59,006
Remaining individualsnot grpmax-eligible	0.00161%	62,156
South Asian	0.00112%	89,654
European (non-Finnish)	0.00051%	196,083

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.Val573=
Coding: c.1719C>T
MANE Select: NM_175875
Type: single nucleotide variant
Location: chr19:45766002 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.21

Full SIX5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SIX5 p.Val573Ile Uncertain significance ★★ ⚠ same residue
SIX5 p.Val573Leu Uncertain significance ★ ⚠ same residue
SIX5 p.Ala408Thr Uncertain significance ★★ ⚠ same type
SIX5 p.Ala411Val Uncertain significance ★★ ⚠ same type
SIX5 p.Ala584Val Uncertain significance ★★ ⚠ same type
SIX5 p.Ala626Thr Uncertain significance ★★ ⚠ same type
SIX5 p.Ala649Ser Uncertain significance ★★ ⚠ same type
SIX5 p.Ala673Thr Uncertain significance ★★ ⚠ same type

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-val573 (accessed [today's date]).

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