Is SIX5 p.Ser637Phe (c.1910C>T) pathogenic?

SIX5 p.Ser637Phe (c.1910C>T) is classified Uncertain significance in SIX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-05-12). AlphaMissense: likely benign (0.163); Ultra-rare (popmax 0.0395%, sas); Associated with branchiootorenal syndrome 2.

What condition is associated with SIX5 p.Ser637Phe (c.1910C>T)?

SIX5 p.Ser637Phe (c.1910C>T) is associated with branchiootorenal syndrome 2 (ClinVar).

How common is SIX5 p.Ser637Phe (c.1910C>T) in the general population?

SIX5 p.Ser637Phe (c.1910C>T) is ultra-rare (popmax 0.0395%, sas) (gnomAD).

What do computational predictors say about SIX5 p.Ser637Phe (c.1910C>T)?

AlphaMissense predicts likely benign (score 0.163) — an in-silico prediction, not a clinical call.

SIX5 p.Ser637Phe

c.1910C>T · VCV3892441

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.163 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0395%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

branchiootorenal syndrome 2

Computational evidence

Protein change
AlphaMissense	0.163	likely benign
REVEL	0.43	indeterminate
SaProt	LLR -7.47	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 2,547 bp · p 3e-11 · regional, not allelic
Overall
CADD	26.5	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 0.0395% South Asian · 36/91,082 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.00231% 37/1,603,802 alleles · ultra-rare exomes 36/1,451,594 · genomes 1/152,208 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0395%	2,530
East Asian	0.00223%	44,876

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.Ser637Phe
Coding: c.1910C>T
MANE Select: NM_175875
Type: single nucleotide variant
Location: chr19:45765811 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.21
Residue 637: the 'disordered' region

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

Disease context

branchiootorenal syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SIX5 p.Ser637Cys Uncertain significance ★ ⚠ same residue
SIX5 p.Ala411Val Uncertain significance ★★ ⚠ same condition
SIX5 p.Ala584Val Uncertain significance ★★ ⚠ same condition
SIX5 p.Ala626Thr Uncertain significance ★★ ⚠ same condition
SIX5 p.Ala649Ser Uncertain significance ★★ ⚠ same condition
SIX5 p.Gln483Pro Uncertain significance ★★ ⚠ same condition
SIX5 p.Gly423Arg Uncertain significance ★★ ⚠ same condition
SIX5 p.Gly500Arg Uncertain significance ★★ same condition

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-ser637phe (accessed [today's date]).

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