Is SIX5 p.Val205Ala (c.614T>C) pathogenic?

SIX5 p.Val205Ala (c.614T>C) is classified Uncertain significance in SIX5 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-04). AlphaMissense: likely pathogenic (0.9742); Absent from gnomAD v4.1; Associated with SIX5-related disorder.

What condition is associated with SIX5 p.Val205Ala (c.614T>C)?

SIX5 p.Val205Ala (c.614T>C) is associated with SIX5-related disorder (ClinVar).

How common is SIX5 p.Val205Ala (c.614T>C) in the general population?

SIX5 p.Val205Ala (c.614T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SIX5 p.Val205Ala (c.614T>C)?

AlphaMissense predicts likely pathogenic (score 0.9742) — an in-silico prediction, not a clinical call.

SIX5 p.Val205Ala

c.614T>C · VCV3344245

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9742 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

SIX5-related disorder

Computational evidence

Protein change
AlphaMissense	0.9742	likely pathogenic
REVEL	0.627	indeterminate
SaProt	LLR -9.11	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 11	GERP -0.031, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 707 bp · p 0.12 · regional, not allelic
Overall
CADD	29.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SIX5
Protein: p.Val205Ala
Coding: c.614T>C
Type: single nucleotide variant
Location: chr19:45768231 (GRCh38)

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

Disease context

SIX5-related disorder

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-val205ala (accessed [today's date]).

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