Is SIX3 p.Gln91Ter (c.271C>T) pathogenic?

SIX3 p.Gln91Ter (c.271C>T) is classified Pathogenic in SIX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-25). Absent from gnomAD v4.1.

How common is SIX3 p.Gln91Ter (c.271C>T) in the general population?

SIX3 p.Gln91Ter (c.271C>T) is absent from gnomAD v4.1 (gnomAD).

SIX3 p.Gln91Ter

c.271C>T · rs2466513754 · VCV2500510

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,596,444)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 1 of 2
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.1, phastCons 1
Overall
CADD	48.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,596,444). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SIX3
Protein: p.Gln91Ter
Coding: c.271C>T
MANE Select: NM_005413
dbSNP: rs2466513754
Type: single nucleotide variant
Location: chr2:44942375 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38
Residue 91: the 'interaction with tle5' region

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

Similar variants

SIX3 p.Ala72Val Uncertain significance ★★ ⚠ same type
SIX3 p.Arg146Cys Uncertain significance ★★ ⚠ same type
SIX3 p.Arg201His Uncertain significance ★★ ⚠ same type
SIX3 p.Arg281Ser Uncertain significance ★★ same type
SIX3 p.Asp205His Uncertain significance ★★ ⚠ same type
SIX3 p.Gly103Arg Uncertain significance ★★ ⚠ same type
SIX3 p.Gly244Cys Uncertain significance ★★ ⚠ same type
SIX3 p.Gly317Ser 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/six3-p-gln91ter (accessed [today's date]).

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