Is SIX3 p.Arg257Pro (c.770G>C) pathogenic?

SIX3 p.Arg257Pro (c.770G>C) is classified Likely pathogenic in SIX3 (ClinVar, Single submitter, 3 submitters; last evaluated 2019-08-02). AlphaMissense: likely pathogenic (1); Absent from gnomAD v4.1; Associated with holoprosencephaly 2.

What condition is associated with SIX3 p.Arg257Pro (c.770G>C)?

SIX3 p.Arg257Pro (c.770G>C) is associated with holoprosencephaly 2 (ClinVar).

How common is SIX3 p.Arg257Pro (c.770G>C) in the general population?

SIX3 p.Arg257Pro (c.770G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SIX3 p.Arg257Pro (c.770G>C)?

AlphaMissense predicts likely pathogenic (score 1) — an in-silico prediction, not a clinical call.

SIX3 p.Arg257Pro

c.770G>C · rs121917879 · VCV6094

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

holoprosencephaly 2

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic ✓ concordant with ClinVar
REVEL	0.882	moderately pathogenic-leaning
SaProt	LLR -14.97	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.23	constrained · MANE · 138 bp · p 4.6e-10 · regional, not allelic
Overall
CADD	35.0	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.Arg257Pro
Coding: c.770G>C
MANE Select: NM_005413
dbSNP: rs121917879
Type: single nucleotide variant
Location: chr2:44942874 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38
Residue 257: a DNA-binding region; a UniProt-annotated variant site (in hpe2); a UniProt-annotated variant site (in hpe2; significantly decreased interaction with nr4a3; significantly decreased its ability to activate nr4a3)

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

Disease context

holoprosencephaly 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SIX3 p.Arg257Gly Uncertain significance ★ ⚠ same residue
SIX3 p.Ala72Val Uncertain significance ★★ ⚠ same condition
SIX3 p.Arg146Cys Uncertain significance ★★ ⚠ same condition
SIX3 p.Arg201His Uncertain significance ★★ ⚠ same condition
SIX3 p.Arg281Ser Uncertain significance ★★ same condition
SIX3 p.Asp205His Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly103Arg Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly244Cys Uncertain significance ★★ ⚠ 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-arg257pro (accessed [today's date]).

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