Is SIX5 p.Pro699Ser (c.2095C>T) pathogenic?

SIX5 p.Pro699Ser (c.2095C>T) is classified Uncertain significance in SIX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-31). AlphaMissense: likely benign (0.075); Absent from gnomAD v4.1.

How common is SIX5 p.Pro699Ser (c.2095C>T) in the general population?

SIX5 p.Pro699Ser (c.2095C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SIX5 p.Pro699Ser (c.2095C>T)?

AlphaMissense predicts likely benign (score 0.075) — an in-silico prediction, not a clinical call.

SIX5 p.Pro699Ser

c.2095C>T · rs2513597819 · VCV2531777

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.075 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.075	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -6.72	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 2.2	GERP 1.4, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 2,547 bp · p 3e-11 · regional, not allelic
Overall
CADD	15.17	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

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.Pro699Ser
Coding: c.2095C>T
MANE Select: NM_175875
dbSNP: rs2513597819
Type: single nucleotide variant
Location: chr19:45765626 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.21

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

Similar variants

SIX5 p.Pro699Arg Uncertain significance ★ ⚠ same residue
SIX5 p.Pro699= Likely benign ★ same residue
SIX5 p.Ala408Thr Uncertain significance ★★ ⚠ same type
SIX5 p.Ala411Val Uncertain significance ★★ ⚠ same type
SIX5 p.Ala584Val Uncertain significance ★★ ⚠ same type
SIX5 p.Ala626Thr Uncertain significance ★★ ⚠ same type
SIX5 p.Ala649Ser Uncertain significance ★★ ⚠ same type
SIX5 p.Ala673Thr Uncertain significance ★★ ⚠ same type

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-pro699ser (accessed [today's date]).

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