Is SIX5 p.Ala499= (c.1497C>T) pathogenic?

SIX5 p.Ala499= (c.1497C>T) is classified Likely benign in SIX5 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-10-05). Ultra-rare (popmax 0.0708%, eas).

How common is SIX5 p.Ala499= (c.1497C>T) in the general population?

SIX5 p.Ala499= (c.1497C>T) is ultra-rare (popmax 0.0708%, eas) (gnomAD).

SIX5 p.Ala499=

c.1497C>T · rs372106524 · VCV1316342

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0708%, 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 -3.2
Overall
CADD	9.212	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0708% East Asian · 29/40,970 alleles

Filtering AF 0.0506% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0437%

Overall 0.00397% 61/1,536,420 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0708%	1,413
African / African-American	0.00686%	14,572
European (non-Finnish)	0.0022%	45,555
Remaining individualsnot grpmax-eligible	0.00168%	59,350
South Asian	0.00122%	82,188

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.Ala499=
Coding: c.1497C>T
MANE Select: NM_175875
dbSNP: rs372106524
Type: single nucleotide variant
Location: chr19:45766462 (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.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
SIX5 p.Asp698Glu 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-ala499 (accessed [today's date]).

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