Is PHOX2A p.Leu52= (c.156C>T) pathogenic?

PHOX2A p.Leu52= (c.156C>T) is classified Benign in PHOX2A (ClinVar, Multiple submitters, 2 submitters). Low-frequency (popmax 3.3%, nfe).

How common is PHOX2A p.Leu52= (c.156C>T) in the general population?

PHOX2A p.Leu52= (c.156C>T) is low-frequency (popmax 3.3%, nfe) (gnomAD).

PHOX2A p.Leu52=

c.156C>T · rs182932220 · VCV259655

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.3%, nfe)

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 3.7	GERP -3.2, phastCons 1
Overall
CADD	12.13	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.3% European (non-Finnish) · 33,027/999,966 alleles

Filtering AF 3.27% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.26%

Overall 3.11% 39,303/1,261,934 alleles · low-frequency exomes 35,313/1,109,656 · genomes 3,990/152,278 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	7.24%	14
Amishnot grpmax-eligible	4.39%	23
Ashkenazi Jewishnot grpmax-eligible	4.06%	25
European (non-Finnish)grpmax	3.3%	30
Remaining individualsnot grpmax-eligible	2.59%	39
Middle Eastern	1.81%	55
South Asian	1.71%	58
Admixed American	1.2%	83
African / African-American	0.541%	185
East Asian	0.453%	221

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PHOX2A
Protein: p.Leu52=
Coding: c.156C>T
MANE Select: NM_005169
dbSNP: rs182932220
Type: single nucleotide variant
Location: chr11:72243849 (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

Similar variants

PHOX2A p.Ala72Val Uncertain significance ★★ ⚠ same type
PHOX2A c.-19G>A 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
PHOX2A p.Ala61Asp Uncertain significance ★ ⚠ same type
PHOX2A p.Ala68Pro 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-leu52 (accessed [today's date]).

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