Is SIX5 p.Asp715= (c.2145C>T) pathogenic?

SIX5 p.Asp715= (c.2145C>T) is classified Likely benign in SIX5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-06). Ultra-rare (popmax 0.02%, amr).

How common is SIX5 p.Asp715= (c.2145C>T) in the general population?

SIX5 p.Asp715= (c.2145C>T) is ultra-rare (popmax 0.02%, amr) (gnomAD).

SIX5 p.Asp715=

c.2145C>T · rs747106145 · VCV2150445

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

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 -16	GERP -3.1
Overall
CADD	0.006	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% Admixed American · 12/60,018 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.0062% 100/1,613,334 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.108%	925
Admixed Americangrpmax	0.02%	5,002
Remaining individualsnot grpmax-eligible	0.008%	12,500
East Asian	0.00669%	14,959
African / African-American	0.00533%	18,761
European (non-Finnish)	0.00347%	28,781
South Asian	0.00329%	30,362

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp715=
Coding: c.2145C>T
MANE Select: NM_175875
dbSNP: rs747106145
Type: single nucleotide variant
Location: chr19:45765576 (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-asp715 (accessed [today's date]).

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