Is SIX5 p.Pro73Ser (c.217C>T) pathogenic?

SIX5 p.Pro73Ser (c.217C>T) is classified Uncertain significance in SIX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-26). AlphaMissense: likely benign (0.067); Ultra-rare (popmax 0.0215%, sas).

How common is SIX5 p.Pro73Ser (c.217C>T) in the general population?

SIX5 p.Pro73Ser (c.217C>T) is ultra-rare (popmax 0.0215%, sas) (gnomAD).

What do computational predictors say about SIX5 p.Pro73Ser (c.217C>T)?

AlphaMissense predicts likely benign (score 0.067) — an in-silico prediction, not a clinical call.

SIX5 p.Pro73Ser

c.217C>T · rs893160207 · VCV2043065

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.067 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0215%, sas)

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	0.067	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -6.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.2	GERP -3.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 707 bp · p 0.12 · regional, not allelic
Overall
CADD	16.19	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 0.0215% South Asian · 7/32,592 alleles

Filtering AF 0.00998% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0071%

Overall 0.00149% 19/1,273,604 alleles · ultra-rare exomes 16/1,122,040 · genomes 3/151,564 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0215%	4,656
Admixed American	0.00424%	23,574
Remaining individualsnot grpmax-eligible	0.0042%	23,812
European (non-Finnish)	0.000884%	113,116

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.Pro73Ser
Coding: c.217C>T
MANE Select: NM_175875
dbSNP: rs893160207
Type: single nucleotide variant
Location: chr19:45768628 (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-pro73ser (accessed [today's date]).

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