Is SIX3 p.Arg4Cys (c.10C>T) pathogenic?

SIX3 p.Arg4Cys (c.10C>T) is classified Uncertain significance in SIX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-16). AlphaMissense: likely pathogenic (0.608); Absent from gnomAD v4.1.

How common is SIX3 p.Arg4Cys (c.10C>T) in the general population?

SIX3 p.Arg4Cys (c.10C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SIX3 p.Arg4Cys (c.10C>T)?

AlphaMissense predicts likely pathogenic (score 0.608) — an in-silico prediction, not a clinical call.

SIX3 p.Arg4Cys

c.10C>T · VCV4954858

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.608 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.608	likely pathogenic
REVEL	0.615	indeterminate
SaProt	LLR -6.70	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 230 bp · p 0.3 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SIX3
Protein: p.Arg4Cys
Coding: c.10C>T
MANE Select: NM_005413
Type: single nucleotide variant
Location: chr2:44942114 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38

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-arg4cys (accessed [today's date]).

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