Is UNC119 p.Pro109Ser (c.325C>T) pathogenic?

UNC119 p.Pro109Ser (c.325C>T) is classified Uncertain significance in UNC119 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-31). AlphaMissense: likely benign (0.1376); Ultra-rare (popmax 0.0165%, mid).

How common is UNC119 p.Pro109Ser (c.325C>T) in the general population?

UNC119 p.Pro109Ser (c.325C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about UNC119 p.Pro109Ser (c.325C>T)?

AlphaMissense predicts likely benign (score 0.1376) — an in-silico prediction, not a clinical call.

UNC119 p.Pro109Ser

c.325C>T · rs576152675 · VCV2001405

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1376 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1376	likely benign
REVEL	0.401	indeterminate
SaProt	LLR -7.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -0.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 5,257 bp · p 0.44 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,056 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000372% 6/1,614,102 alleles · ultra-rare exomes 6/1,461,778 · genomes 0/152,324 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
South Asian	0.0011%	91,090
European (non-Finnish)	0.000339%	294,990

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.Pro109Ser
Coding: c.325C>T
MANE Select: NM_005148
dbSNP: rs576152675
Type: single nucleotide variant
Location: chr17:28548601 (GRCh38)
Gene constraint: LOEUF 1.139 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.03 · 9 PDB
Residue 109: 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)

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

Similar variants

UNC119 p.Pro109Ala Uncertain significance ★ ⚠ same residue
UNC119 p.Arg113Trp Uncertain significance ★★ ⚠ same type
UNC119 p.Arg118Gln Uncertain significance ★★ ⚠ same type
UNC119 p.Arg118Trp Uncertain significance ★★ ⚠ same type
UNC119 p.Arg119Trp Uncertain significance ★★ ⚠ same type
UNC119 p.Arg127Cys Uncertain significance ★★ ⚠ same type
UNC119 p.Arg127His Uncertain significance ★★ ⚠ same type
UNC119 p.Arg130Cys 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/unc119-p-pro109ser (accessed [today's date]).

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