Is SIX5 p.Pro151Ser (c.451C>T) pathogenic?

SIX5 p.Pro151Ser (c.451C>T) is classified Uncertain significance in SIX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-22). AlphaMissense: likely benign (0.2105); Very rare (popmax 0.00163%, nfe).

How common is SIX5 p.Pro151Ser (c.451C>T) in the general population?

SIX5 p.Pro151Ser (c.451C>T) is very rare (popmax 0.00163%, nfe) (gnomAD).

What do computational predictors say about SIX5 p.Pro151Ser (c.451C>T)?

AlphaMissense predicts likely benign (score 0.2105) — an in-silico prediction, not a clinical call.

SIX5 p.Pro151Ser

c.451C>T · VCV4691684

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2105 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00163%, nfe)

Missense predictors

0/3 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	0.2105	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -7.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.2	GERP -0.63, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 707 bp · p 0.12 · regional, not allelic
Overall
CADD	26.4	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

Grpmax group 0.00163% European (non-Finnish) · 19/1,165,590 alleles

Filtering AF 0.00104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00084%

Overall 0.00127% 20/1,572,438 alleles · very rare exomes 20/1,420,146 · genomes 0/152,292 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00163%	61,347
South Asian	0.00114%	87,888

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.Pro151Ser
Coding: c.451C>T
MANE Select: NM_175875
Type: single nucleotide variant
Location: chr19:45768394 (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-pro151ser (accessed [today's date]).

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