Is SIX3 p.Pro74Arg (c.221C>G) pathogenic?

SIX3 p.Pro74Arg (c.221C>G) is classified Uncertain significance in SIX3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-02). AlphaMissense: likely benign (0.1007); Ultra-rare (popmax 0.0195%, nfe); Associated with holoprosencephaly 2.

What condition is associated with SIX3 p.Pro74Arg (c.221C>G)?

SIX3 p.Pro74Arg (c.221C>G) is associated with holoprosencephaly 2 (ClinVar).

How common is SIX3 p.Pro74Arg (c.221C>G) in the general population?

SIX3 p.Pro74Arg (c.221C>G) is ultra-rare (popmax 0.0195%, nfe) (gnomAD).

What do computational predictors say about SIX3 p.Pro74Arg (c.221C>G)?

AlphaMissense predicts likely benign (score 0.1007) — an in-silico prediction, not a clinical call.

SIX3 p.Pro74Arg

c.221C>G · rs771429347 · VCV1463172

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1007 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0195%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

holoprosencephaly 2

Computational evidence

Protein change
AlphaMissense	0.1007	likely benign
REVEL	0.201	benign-leaning
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 230 bp · p 0.3 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0195% European (non-Finnish) · 230/1,177,682 alleles

Filtering AF 0.0174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0166%

Overall 0.0169% 269/1,593,720 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0231%	4,325
European (non-Finnish)grpmax	0.0195%	5,120
Admixed American	0.0167%	5,971
Remaining individualsnot grpmax-eligible	0.0145%	6,898
African / African-American	0.00668%	14,966
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,494
South Asian	0.0033%	30,267

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro74Arg
Coding: c.221C>G
MANE Select: NM_005413
dbSNP: rs771429347
Type: single nucleotide variant
Location: chr2:44942325 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38
Residue 74: the 'interaction with tle5' region

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.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
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-pro74arg (accessed [today's date]).

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