Is PHOX2A p.Leu59Val (c.175C>G) pathogenic?

PHOX2A p.Leu59Val (c.175C>G) is classified Uncertain significance in PHOX2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely benign (0.1385); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PHOX2A p.Leu59Val (c.175C>G)?

PHOX2A p.Leu59Val (c.175C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PHOX2A p.Leu59Val (c.175C>G) in the general population?

PHOX2A p.Leu59Val (c.175C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHOX2A p.Leu59Val (c.175C>G)?

AlphaMissense predicts likely benign (score 0.1385) — an in-silico prediction, not a clinical call.

PHOX2A p.Leu59Val

c.175C>G · VCV4136070

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1385 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1385	likely benign
REVEL	0.432	indeterminate
SaProt	LLR -7.93	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 3,947 bp · p 0.076 · regional, not allelic
Overall
CADD	25.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PHOX2A
Protein: p.Leu59Val
Coding: c.175C>G
MANE Select: NM_005169
Type: single nucleotide variant
Location: chr11:72243830 (GRCh38)
Gene constraint: LOEUF 1.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.49

Full PHOX2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHOX2A p.Ala152Gly Uncertain significance ★ ⚠ same condition
PHOX2A p.Ala158Glu Uncertain significance ★ ⚠ same condition
PHOX2A p.Ala278Asp Uncertain significance ★ same condition
PHOX2A p.Ala278Val Uncertain significance ★ ⚠ same condition
PHOX2A p.Ala61Asp Uncertain significance ★ ⚠ same condition
PHOX2A p.Ala68Pro Uncertain significance ★ ⚠ same condition
PHOX2A p.Arg169Cys Uncertain significance ★ ⚠ same condition
PHOX2A p.Arg63His Uncertain significance ★ 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/phox2a-p-leu59val (accessed [today's date]).

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