Is SIX5 p.Arg128Ser (c.382C>A) pathogenic?

SIX5 p.Arg128Ser (c.382C>A) is classified Uncertain significance in SIX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-27). AlphaMissense: likely pathogenic (0.9977); Very rare (popmax 0.00175%, nfe).

How common is SIX5 p.Arg128Ser (c.382C>A) in the general population?

SIX5 p.Arg128Ser (c.382C>A) is very rare (popmax 0.00175%, nfe) (gnomAD).

What do computational predictors say about SIX5 p.Arg128Ser (c.382C>A)?

AlphaMissense predicts likely pathogenic (score 0.9977) — an in-silico prediction, not a clinical call.

SIX5 p.Arg128Ser

c.382C>A · rs1350446479 · VCV2967044

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9977	likely pathogenic
REVEL	0.687	pathogenic-leaning
SaProt	LLR -9.41	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.2	GERP -3.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 707 bp · p 0.12 · regional, not allelic
Overall
CADD	28.9	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 0.00175% European (non-Finnish) · 20/1,144,644 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000927%

Overall 0.00137% 21/1,529,640 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00175%	57,232
Remaining individualsnot grpmax-eligible	0.00168%	59,564

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.Arg128Ser
Coding: c.382C>A
dbSNP: rs1350446479
Type: single nucleotide variant
Location: chr19:45768463 (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-arg128ser (accessed [today's date]).

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