Is SIX6 p.Pro38= (c.114C>T) pathogenic?

SIX6 p.Pro38= (c.114C>T) is classified Likely benign in SIX6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). Rare (popmax 0.107%, eas).

How common is SIX6 p.Pro38= (c.114C>T) in the general population?

SIX6 p.Pro38= (c.114C>T) is rare (popmax 0.107%, eas) (gnomAD).

SIX6 p.Pro38=

c.114C>T · rs185399510 · VCV2730051

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.107%, eas)

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.23	GERP -3.8, phastCons 0.26
Overall
CADD	11.31	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.107% East Asian · 48/44,880 alleles

Filtering AF 0.0829% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0743%

Overall 0.00318% 51/1,605,796 alleles · rare exomes 41/1,453,444 · genomes 10/152,352 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.107%	935
Remaining individualsnot grpmax-eligible	0.0016%	62,458
European (non-Finnish)	0.000169%	589,984

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: SIX6
Protein: p.Pro38=
Coding: c.114C>T
MANE Select: NM_007374
dbSNP: rs185399510
Type: single nucleotide variant
Location: chr14:60509512 (GRCh38)

Full SIX6 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/six6-p-pro38 (accessed [today's date]).

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