Is SIX5 p.Arg224Pro (c.671G>C) pathogenic?

SIX5 p.Arg224Pro (c.671G>C) is classified Uncertain significance in SIX5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-24). AlphaMissense: likely pathogenic (0.6124); Ultra-rare (popmax 0.0201%, eas).

How common is SIX5 p.Arg224Pro (c.671G>C) in the general population?

SIX5 p.Arg224Pro (c.671G>C) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about SIX5 p.Arg224Pro (c.671G>C)?

AlphaMissense predicts likely pathogenic (score 0.6124) — an in-silico prediction, not a clinical call.

SIX5 p.Arg224Pro

c.671G>C · rs771658903 · VCV2336439

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6124 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6124	likely pathogenic
REVEL	0.641	indeterminate
SaProt	LLR -4.92	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.5	GERP -0.37, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 707 bp · p 0.12 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.0201% East Asian · 9/44,870 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.000558% 9/1,612,616 alleles · ultra-rare

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: SIX5
Protein: p.Arg224Pro
Coding: c.671G>C
dbSNP: rs771658903
Type: single nucleotide variant
Location: chr19:45768174 (GRCh38)

Full SIX5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/six5-p-arg224pro (accessed [today's date]).

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