Is SIX5 p.Pro635Ser (c.1903C>T) pathogenic?

SIX5 p.Pro635Ser (c.1903C>T) is classified Benign in SIX5 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.068); Common (popmax 66.2%, eas) — too common for a highly-penetrant pathogenic allele; Associated with branchiootorenal syndrome 2.

What condition is associated with SIX5 p.Pro635Ser (c.1903C>T)?

SIX5 p.Pro635Ser (c.1903C>T) is associated with branchiootorenal syndrome 2 (ClinVar).

What do computational predictors say about SIX5 p.Pro635Ser (c.1903C>T)?

AlphaMissense predicts likely benign (score 0.068) — an in-silico prediction, not a clinical call.

SIX5 p.Pro635Ser

Q: How common is SIX5 p.Pro635Ser (c.1903C>T) in the general population?

SIX5 p.Pro635Ser (c.1903C>T) is common (popmax 66.2%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1903C>T · rs2014576 · VCV262912

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.068 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 66.2%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

branchiootorenal syndrome 2

Computational evidence

Protein change
AlphaMissense	0.068	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -6.42	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 2.3	GERP -0.87, phastCons 0.99
Regional constraint	o/e 1.27	unconstrained · MANE · 2,547 bp · p 3e-11 · regional, not allelic
Overall
CADD	14.03	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 66.2% East Asian · 29,683/44,840 alleles

Filtering AF 65.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 65.3%

Overall 46.5% 745,197/1,602,080 alleles · common exomes 677,894/1,450,050 · genomes 67,303/152,030 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	66.2%	2
Admixed American	63.4%	2
South Asian	58.1%	2
Finnishnot grpmax-eligible	47.4%	2
Remaining individualsnot grpmax-eligible	45.9%	2
European (non-Finnish)	45%	2
Middle Eastern	44.7%	2
Ashkenazi Jewishnot grpmax-eligible	36.9%	3
African / African-American	34.5%	3
Amishnot grpmax-eligible	27.7%	4

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.Pro635Ser
Coding: c.1903C>T
MANE Select: NM_175875
dbSNP: rs2014576
Type: single nucleotide variant
Location: chr19:45765818 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.21
Residue 635: a UniProt-annotated variant site (in); 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.Pro635_Phe636delinsSer Uncertain significance ★ same residue
SIX5 p.Pro635Leu 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

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-pro635ser (accessed [today's date]).

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