Is SIX3 p.Arg281Ser (c.841C>A) pathogenic?

SIX3 p.Arg281Ser (c.841C>A) is classified Uncertain significance in SIX3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-03). AlphaMissense: ambiguous (0.4194); Very rare (popmax 0.00232%, eas); Associated with Inborn genetic diseases.

What condition is associated with SIX3 p.Arg281Ser (c.841C>A)?

SIX3 p.Arg281Ser (c.841C>A) is associated with Inborn genetic diseases, holoprosencephaly 2 (ClinVar).

How common is SIX3 p.Arg281Ser (c.841C>A) in the general population?

SIX3 p.Arg281Ser (c.841C>A) is very rare (popmax 0.00232%, eas) (gnomAD).

What do computational predictors say about SIX3 p.Arg281Ser (c.841C>A)?

AlphaMissense predicts ambiguous (score 0.4194) — an in-silico prediction, not a clinical call.

SIX3 p.Arg281Ser

c.841C>A · rs1197394985 · VCV2807273

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4194 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00232%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4194	ambiguous
REVEL	0.357	indeterminate
SaProt	LLR -4.83	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.95, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 189 bp · p 0.083 · regional, not allelic
Overall
CADD	22.9	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

Grpmax group 0.00232% East Asian · 1/43,052 alleles

Filtering AF 0.000433% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000316%

Overall 0.000698% 11/1,575,982 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00232%	43,052
European (non-Finnish)	0.000856%	116,799

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.Arg281Ser
Coding: c.841C>A
MANE Select: NM_005413
dbSNP: rs1197394985
Type: single nucleotide variant
Location: chr2:44944602 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38
Residue 281: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: holoprosencephaly 2

Similar variants

SIX3 p.Arg281= Likely benign ★ 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.Asp205His Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly103Arg Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly244Cys Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly317Ser 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-arg281ser (accessed [today's date]).

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