Is SIX5 p.Ser78Phe (c.233C>T) pathogenic?

SIX5 p.Ser78Phe (c.233C>T) is classified Likely benign in SIX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-03-08). AlphaMissense: likely benign (0.2497); Very rare (popmax 0.00314%, eas).

How common is SIX5 p.Ser78Phe (c.233C>T) in the general population?

SIX5 p.Ser78Phe (c.233C>T) is very rare (popmax 0.00314%, eas) (gnomAD).

What do computational predictors say about SIX5 p.Ser78Phe (c.233C>T)?

AlphaMissense predicts likely benign (score 0.2497) — an in-silico prediction, not a clinical call.

SIX5 p.Ser78Phe

c.233C>T · rs2146209512 · VCV1318058

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2497 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2497	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -9.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 707 bp · p 0.12 · regional, not allelic
Overall
CADD	24.8	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 0.00314% East Asian · 1/31,874 alleles

Filtering AF 0.000492% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000358%

Overall 0.000964% 11/1,140,664 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00314%	31,874
European (non-Finnish)	0.000972%	102,867

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.Ser78Phe
Coding: c.233C>T
dbSNP: rs2146209512
Type: single nucleotide variant
Location: chr19:45768612 (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-ser78phe (accessed [today's date]).

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