Is PDE6A p.Leu386Phe (c.1156C>T) pathogenic?

PDE6A p.Leu386Phe (c.1156C>T) is classified Uncertain significance in PDE6A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). AlphaMissense: likely pathogenic (0.9556); Very rare (popmax 0.004%, afr).

How common is PDE6A p.Leu386Phe (c.1156C>T) in the general population?

PDE6A p.Leu386Phe (c.1156C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about PDE6A p.Leu386Phe (c.1156C>T)?

AlphaMissense predicts likely pathogenic (score 0.9556) — an in-silico prediction, not a clinical call.

PDE6A p.Leu386Phe

c.1156C>T · rs1247715440 · VCV1370571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9556 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9556	likely pathogenic
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -8.61	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 77 kb · p 0.94 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/75,038 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000494%

Overall 0.000205% 3/1,461,758 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.Leu386Phe
Coding: c.1156C>T
MANE Select: NM_000440
dbSNP: rs1247715440
Type: single nucleotide variant
Location: chr5:149899482 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.80
Residue 386: the gaf 2 domain

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

Similar variants

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
PDE6A c.2027+2T>G 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-leu386phe (accessed [today's date]).

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