Is SIX1 p.Arg175Pro (c.524G>C) pathogenic?

SIX1 p.Arg175Pro (c.524G>C) is classified Uncertain significance in SIX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-19). AlphaMissense: likely pathogenic (1); No allele count reported in gnomAD v4.1 (AN 1,614,100).

How common is SIX1 p.Arg175Pro (c.524G>C) in the general population?

SIX1 p.Arg175Pro (c.524G>C) is no allele count reported in gnomAD v4.1 (AN 1,614,100) (gnomAD).

What do computational predictors say about SIX1 p.Arg175Pro (c.524G>C)?

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

SIX1 p.Arg175Pro

c.524G>C · rs2140240984 · VCV1310217

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,100)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic
REVEL	0.974	strongly pathogenic-leaning
SaProt	LLR -15.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 2,558 bp · p 0.27 · regional, not allelic
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

No allele count reported in gnomAD v4.1 (AN 1,614,100). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SIX1
Protein: p.Arg175Pro
Coding: c.524G>C
MANE Select: NM_005982
dbSNP: rs2140240984
Type: single nucleotide variant
Location: chr14:60648666 (GRCh38)

Full SIX1 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/six1-p-arg175pro (accessed [today's date]).

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