Is SIX3 p.Asp331= (c.993T>C) pathogenic?

SIX3 p.Asp331= (c.993T>C) is classified Likely benign in SIX3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-03-31). Ultra-rare (popmax 0.0165%, mid); Associated with SIX3-related disorder.

What condition is associated with SIX3 p.Asp331= (c.993T>C)?

SIX3 p.Asp331= (c.993T>C) is associated with SIX3-related disorder (ClinVar).

How common is SIX3 p.Asp331= (c.993T>C) in the general population?

SIX3 p.Asp331= (c.993T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

SIX3 p.Asp331=

c.993T>C · rs1276811710 · VCV3030585

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

SIX3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.55 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5	GERP -0.6, phastCons 1
Overall
CADD	12.52	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,044 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000349% 5/1,432,412 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,044
European (non-Finnish)	0.000341%	293,185

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: SIX3
Protein: p.Asp331=
Coding: c.993T>C
MANE Select: NM_005413
dbSNP: rs1276811710
Type: single nucleotide variant
Location: chr2:44944754 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38
Residue 331: the 'disordered' region

Full SIX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SIX3-related disorder

Similar variants

SIX3 p.Asp331Glu Uncertain significance ★ ⚠ same residue
SIX3 p.Pro289Thr Uncertain significance ★★ ⚠ same condition
SIX3 c.806+2T>C Likely pathogenic ★ same condition
SIX3 p.Arg258Trp Likely pathogenic ★ same condition
SIX3 p.Gln241Ter Pathogenic ★ same condition
SIX3 p.Gly287Ser Uncertain significance ★ ⚠ same condition
SIX3 p.Ser130Pro Uncertain significance ★ ⚠ same condition
SIX3 p.Gly33= Likely benign same condition

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/six3-p-asp331 (accessed [today's date]).

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