Is SIX2 p.Pro236Leu (c.707C>T) pathogenic?

SIX2 p.Pro236Leu (c.707C>T) is classified Uncertain significance in SIX2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-18). AlphaMissense: likely benign (0.0811); Ultra-rare (popmax 0.0387%, nfe); Associated with congenital anomaly of kidney and urinary tract.

What condition is associated with SIX2 p.Pro236Leu (c.707C>T)?

SIX2 p.Pro236Leu (c.707C>T) is associated with congenital anomaly of kidney and urinary tract (ClinVar).

How common is SIX2 p.Pro236Leu (c.707C>T) in the general population?

SIX2 p.Pro236Leu (c.707C>T) is ultra-rare (popmax 0.0387%, nfe) (gnomAD).

What do computational predictors say about SIX2 p.Pro236Leu (c.707C>T)?

AlphaMissense predicts likely benign (score 0.0811) — an in-silico prediction, not a clinical call.

SIX2 p.Pro236Leu

c.707C>T · rs372153489 · VCV224349

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0811 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0387%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital anomaly of kidney and urinary tract

Computational evidence

Protein change
AlphaMissense	0.0811	likely benign
REVEL	0.328	indeterminate
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,568 bp · p 0.84 · regional, not allelic
Overall
CADD	22.5	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 0.0387% European (non-Finnish) · 457/1,179,882 alleles

Filtering AF 0.0358% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0346%

Overall 0.0307% 495/1,613,892 alleles · ultra-rare exomes 462/1,461,642 · genomes 33/152,250 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0387%	2,582
Remaining individualsnot grpmax-eligible	0.024%	4,165
Admixed American	0.0183%	5,455
East Asian	0.0111%	8,977
African / African-American	0.00667%	14,989
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
South Asian	0.0011%	91,090

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: SIX2
Protein: p.Pro236Leu
Coding: c.707C>T
MANE Select: NM_016932
dbSNP: rs372153489
Type: single nucleotide variant
Location: chr2:45006339 (GRCh38)
Gene constraint: LOEUF 1.24 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.99
Residue 236: the 'disordered' region

Full SIX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital anomaly of kidney and urinary tract — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SIX2 p.Asn280Ser Uncertain significance ★★ ⚠ same type
SIX2 p.Gly220Val Uncertain significance ★★ ⚠ same type
SIX2 p.Gly261Ser Uncertain significance ★★ ⚠ same type
SIX2 p.Pro235Leu Uncertain significance ★★ ⚠ same type
SIX2 p.Pro250Leu Uncertain significance ★★ ⚠ same type
SIX2 p.Pro258Leu Uncertain significance ★★ ⚠ same type
SIX2 p.Ser212Trp Uncertain significance ★★ ⚠ same type
SIX2 p.Ser253Gly 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/six2-p-pro236leu (accessed [today's date]).

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