Is SIX5 p.Phe208= (c.624C>T) pathogenic?

SIX5 p.Phe208= (c.624C>T) is classified Benign/Likely benign in SIX5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-29). Rare (popmax 0.318%, afr).

How common is SIX5 p.Phe208= (c.624C>T) in the general population?

SIX5 p.Phe208= (c.624C>T) is rare (popmax 0.318%, afr) (gnomAD).

SIX5 p.Phe208=

c.624C>T · rs140161317 · VCV514988

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.318%, afr)

⚠ 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 12	GERP 2.1, phastCons 1
Overall
CADD	14.44	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.318% African / African-American · 239/75,056 alleles

Filtering AF 0.285% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.272%

Overall 0.0156% 252/1,613,248 alleles · rare exomes 143/1,460,880 · genomes 109/152,368 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.318%	314
Middle Eastern	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.0128%	7,808
Admixed American	0.00334%	29,982
South Asian	0.0022%	45,512

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.Phe208=
Coding: c.624C>T
MANE Select: NM_175875
dbSNP: rs140161317
Type: single nucleotide variant
Location: chr19:45768221 (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-phe208 (accessed [today's date]).

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