Is SIX5 p.Ala580= (c.1740C>T) pathogenic?

SIX5 p.Ala580= (c.1740C>T) is classified Likely benign in SIX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). Ultra-rare (popmax 0.0332%, mid).

How common is SIX5 p.Ala580= (c.1740C>T) in the general population?

SIX5 p.Ala580= (c.1740C>T) is ultra-rare (popmax 0.0332%, mid) (gnomAD).

SIX5 p.Ala580=

c.1740C>T · rs776945033 · VCV1942737

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0332%, mid)

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 0.54	GERP -3, phastCons 0.96
Overall
CADD	1.043	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0332% Middle Eastern · 2/6,016 alleles

Filtering AF 0.00586% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00132% 19/1,442,390 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0332%	3,008
Admixed American	0.00518%	19,293
South Asian	0.00455%	21,974
Remaining individualsnot grpmax-eligible	0.00162%	61,706
European (non-Finnish)	0.000768%	130,187

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.Ala580=
Coding: c.1740C>T
MANE Select: NM_175875
dbSNP: rs776945033
Type: single nucleotide variant
Location: chr19:45765981 (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.Ala580Val Conflicting classifications of pathogenicity ★ ⚠ 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
SIX5 p.Ala722Gly 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-ala580 (accessed [today's date]).

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