Is PROX1 p.Pro304= (c.912A>C) pathogenic?

PROX1 p.Pro304= (c.912A>C) is classified Likely benign in PROX1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-12-16). Low-frequency (popmax 1.01%, eas); Associated with PROX1-related disorder.

What condition is associated with PROX1 p.Pro304= (c.912A>C)?

PROX1 p.Pro304= (c.912A>C) is associated with PROX1-related disorder (ClinVar).

How common is PROX1 p.Pro304= (c.912A>C) in the general population?

PROX1 p.Pro304= (c.912A>C) is low-frequency (popmax 1.01%, eas) (gnomAD).

PROX1 p.Pro304=

c.912A>C · rs188226653 · VCV3049248

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 1.01%, eas)

Conditions

PROX1-related disorder

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 -14	GERP -5.2
Overall
CADD	0.035	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.01% East Asian · 452/44,862 alleles

Filtering AF 0.931% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.901%

Overall 0.0297% 479/1,614,116 alleles · low-frequency exomes 451/1,461,876 · genomes 28/152,240 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.01%	99
Remaining individualsnot grpmax-eligible	0.04%	2,500
European (non-Finnish)	0.000169%	590,012

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: PROX1
Protein: p.Pro304=
Coding: c.912A>C
MANE Select: NM_001270616
dbSNP: rs188226653
Type: single nucleotide variant
Location: chr1:213997447 (GRCh38)
Gene constraint: LOEUF 0.222 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.63 · 1 PDB

Full PROX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PROX1-related disorder

Similar variants

PROX1 c.*4T>A Likely benign same condition
PROX1 p.Cys300= Likely benign same condition
PROX1 p.His336Pro Likely benign same condition
PROX1 p.Leu314= Benign same condition
PROX1 p.His61= Likely benign ★★ same type
PROX1 p.Ala288Val Uncertain significance ★ ⚠ same type
PROX1 p.Ala391Thr Uncertain significance ★ ⚠ same type
PROX1 p.Ala698Ser 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/prox1-p-pro304 (accessed [today's date]).

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