Is SIX3 p.Phe145= (c.435C>T) pathogenic?

SIX3 p.Phe145= (c.435C>T) is classified Likely benign in SIX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-09-29). Very rare (popmax 0.00133%, afr).

How common is SIX3 p.Phe145= (c.435C>T) in the general population?

SIX3 p.Phe145= (c.435C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

SIX3 p.Phe145=

c.435C>T · rs750603655 · VCV772264

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 1, phastCons 1
Overall
CADD	14.93	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,932 alleles

Overall 6.26e-05% 1/1,598,538 alleles · very rare exomes 0/1,446,318 · genomes 1/152,220 · joint denominator

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: SIX3
Protein: p.Phe145=
Coding: c.435C>T
MANE Select: NM_005413
dbSNP: rs750603655
Type: single nucleotide variant
Location: chr2:44942539 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38

Full SIX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SIX3 p.Ala72Val Uncertain significance ★★ ⚠ same type
SIX3 p.Arg146Cys Uncertain significance ★★ ⚠ same type
SIX3 p.Arg201His Uncertain significance ★★ ⚠ same type
SIX3 p.Arg281Ser Uncertain significance ★★ same type
SIX3 p.Asp205His Uncertain significance ★★ ⚠ same type
SIX3 p.Gly103Arg Uncertain significance ★★ ⚠ same type
SIX3 p.Gly244Cys Uncertain significance ★★ ⚠ same type
SIX3 p.Gly317Ser 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/six3-p-phe145 (accessed [today's date]).

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