Is PDE6A p.Ala619Pro (c.1855G>C) pathogenic?

PDE6A p.Ala619Pro (c.1855G>C) is classified Uncertain significance in PDE6A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-10). AlphaMissense: likely pathogenic (0.9938); Very rare (popmax 8.48e-05%, nfe).

How common is PDE6A p.Ala619Pro (c.1855G>C) in the general population?

PDE6A p.Ala619Pro (c.1855G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PDE6A p.Ala619Pro (c.1855G>C)?

AlphaMissense predicts likely pathogenic (score 0.9938) — an in-silico prediction, not a clinical call.

PDE6A p.Ala619Pro

c.1855G>C · rs1752223184 · VCV1434388

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9938	likely pathogenic
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -12.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 77 kb · p 0.94 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.48e-05% European (non-Finnish) · 1/1,179,682 alleles

Overall 6.84e-05% 1/1,461,484 alleles · very rare

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: PDE6A
Protein: p.Ala619Pro
Coding: c.1855G>C
MANE Select: NM_000440
dbSNP: rs1752223184
Type: single nucleotide variant
Location: chr5:149884851 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.80
Residue 619: the pdease domain

Full PDE6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE6A p.Ala619= Likely benign ★ same residue
PDE6A c.1065+2T>A Pathogenic/Likely pathogenic ★★ same type
PDE6A c.1263+1G>T Pathogenic/Likely pathogenic ★★ same type
PDE6A c.1407+1G>C Pathogenic/Likely pathogenic ★★ same type
PDE6A c.1620+1G>A Pathogenic ★★ same type
PDE6A c.1620+2T>A Pathogenic/Likely pathogenic ★★ same type
PDE6A c.1926+1G>A Pathogenic ★★ same type
PDE6A c.1927-1G>C Pathogenic/Likely pathogenic ★★ 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/pde6a-p-ala619pro (accessed [today's date]).

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