Is UNC119 p.Phe221= (c.663C>T) pathogenic?

UNC119 p.Phe221= (c.663C>T) is classified Benign/Likely benign in UNC119 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). Low-frequency (popmax 1.19%, eas); Associated with cone-rod dystrophy.

What condition is associated with UNC119 p.Phe221= (c.663C>T)?

UNC119 p.Phe221= (c.663C>T) is associated with cone-rod dystrophy (ClinVar).

How common is UNC119 p.Phe221= (c.663C>T) in the general population?

UNC119 p.Phe221= (c.663C>T) is low-frequency (popmax 1.19%, eas) (gnomAD).

How is Cone rod dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

UNC119 p.Phe221=

c.663C>T · rs139354163 · VCV322460

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.19%, eas)

Conditions

cone-rod dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.25	GERP -0.2, phastCons 0.91
Overall
CADD	9.085	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.19% East Asian · 535/44,882 alleles

Filtering AF 1.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.08%

Overall 0.0367% 593/1,614,204 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.19%	84
Remaining individualsnot grpmax-eligible	0.0432%	2,315
South Asian	0.00878%	11,386
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
European (non-Finnish)	0.00178%	56,192
Admixed American	0.00167%	60,024

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: UNC119
Protein: p.Phe221=
Coding: c.663C>T
MANE Select: NM_005148
dbSNP: rs139354163
Type: single nucleotide variant
Location: chr17:28547357 (GRCh38)
Gene constraint: LOEUF 1.139 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.03 · 9 PDB
Residue 221: a UniProt-annotated variant site (in cord24; when expressed in transgenic mice, it results in age-dependent fundus lesions, defects in photoreceptor synaptic transmission and retinal degeneration); a UniProt-annotated variant site (in cord24; uncertain significance); the 'required for centrosome localization' region; a β-strand

Full UNC119 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cone-rod dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Cone rod dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

UNC119 p.Arg209His Uncertain significance ★★ ⚠ same condition
UNC119 p.Asp176Asn Uncertain significance ★★ ⚠ same condition
UNC119 p.Leu140Arg Uncertain significance ★★ ⚠ same condition
UNC119 c.220+15G>C Benign ★★ same condition
UNC119 c.437+7C>T Benign/Likely benign ★★ same condition
UNC119 c.*1C>T Benign/Likely benign ★★ same condition
UNC119 p.Arg119Gln Benign/Likely benign ★★ same condition
UNC119 p.Val89= Benign/Likely benign ★★ 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/unc119-p-phe221 (accessed [today's date]).

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