Is HOXA2 p.Pro111= (c.333G>A) pathogenic?

HOXA2 p.Pro111= (c.333G>A) is classified Uncertain significance in HOXA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Very rare (popmax 0.00231%, eas); Associated with bilateral microtia-deafness-cleft palate syndrome.

What condition is associated with HOXA2 p.Pro111= (c.333G>A)?

HOXA2 p.Pro111= (c.333G>A) is associated with bilateral microtia-deafness-cleft palate syndrome (ClinVar).

How common is HOXA2 p.Pro111= (c.333G>A) in the general population?

HOXA2 p.Pro111= (c.333G>A) is very rare (popmax 0.00231%, eas) (gnomAD).

HOXA2 p.Pro111=

c.333G>A · rs1783939614 · VCV909466

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00231%, eas)

Conditions

bilateral microtia-deafness-cleft palate syndrome

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 0.089	GERP -7.1, phastCons 0.38
Overall
CADD	5.698	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00231% East Asian · 1/43,210 alleles

Overall 0.000127% 2/1,571,262 alleles · very rare exomes 2/1,419,066 · genomes 0/152,196 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00231%	43,210
European (non-Finnish)	8.63e-05%	1,158,570

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: HOXA2
Protein: p.Pro111=
Coding: c.333G>A
MANE Select: NM_006735
dbSNP: rs1783939614
Type: single nucleotide variant
Location: chr7:27102168 (GRCh38)
Gene constraint: LOEUF 0.334 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 58.47

Full HOXA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

bilateral microtia-deafness-cleft palate syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HOXA2 p.Asp324Asn Uncertain significance ★★ ⚠ same condition
HOXA2 p.Leu336Val Uncertain significance ★★ ⚠ same condition
HOXA2 p.Pro27Arg Uncertain significance ★★ ⚠ same condition
HOXA2 p.Ser132Thr Uncertain significance ★★ ⚠ same condition
HOXA2 p.Ser269= Uncertain significance ★★ same condition
HOXA2 c.-136A>G Uncertain significance ★ same condition
HOXA2 c.-140T>C Uncertain significance ★ same condition
HOXA2 c.-18G>A 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/hoxa2-p-pro111 (accessed [today's date]).

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