Is PHOX2A p.Ala72Val (c.215C>T) pathogenic?

PHOX2A p.Ala72Val (c.215C>T) is classified Uncertain significance in PHOX2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-04). AlphaMissense: likely benign (0.187); Absent from gnomAD v4.1; Associated with fibrosis of extraocular muscles, congenital, 2.

What condition is associated with PHOX2A p.Ala72Val (c.215C>T)?

PHOX2A p.Ala72Val (c.215C>T) is associated with fibrosis of extraocular muscles, congenital, 2 (ClinVar).

How common is PHOX2A p.Ala72Val (c.215C>T) in the general population?

PHOX2A p.Ala72Val (c.215C>T) is absent from gnomAD v4.1 (gnomAD).

How is Congenital fibrosis of extraocular muscles inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PHOX2A p.Ala72Val (c.215C>T)?

AlphaMissense predicts likely benign (score 0.187) — an in-silico prediction, not a clinical call.

PHOX2A p.Ala72Val

c.215C>T · rs104894269 · VCV6840

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.187 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,247,604)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

fibrosis of extraocular muscles, congenital, 2

Computational evidence

Protein change
AlphaMissense	0.187	likely benign
REVEL	0.636	indeterminate
SaProt	LLR -9.23	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.99	donor gain · deltas
Pangolin	Δ0.68	gain · loss 0.66 · agrees with SpliceAI · independent
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	36.0	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

No allele count reported in gnomAD v4.1 (AN 1,247,604). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PHOX2A
Protein: p.Ala72Val
Coding: c.215C>T
MANE Select: NM_005169
dbSNP: rs104894269
Type: single nucleotide variant
Location: chr11:72243790 (GRCh38)
Gene constraint: LOEUF 1.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.49
Residue 72: a UniProt-annotated variant site (in cfeom2)

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

Disease context

fibrosis of extraocular muscles, congenital, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital fibrosis of extraocular muscles (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

PHOX2A c.217+1G>A Pathogenic same condition
PHOX2A c.406-1G>A Pathogenic same condition
PHOX2A c.-19G>A Benign ★★ same type
PHOX2A p.Leu52= Benign ★★ same type
PHOX2A p.Ala152Gly Uncertain significance ★ ⚠ same type
PHOX2A p.Ala158Glu Uncertain significance ★ ⚠ same type
PHOX2A p.Ala278Asp Uncertain significance ★ same type
PHOX2A p.Ala278Val 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/phox2a-p-ala72val (accessed [today's date]).

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