Is FOXI1 p.Pro324= (c.972G>C) pathogenic?

FOXI1 p.Pro324= (c.972G>C) is classified Conflicting classifications of pathogenicity in FOXI1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-30). Low-frequency (popmax 1.92%, nfe); Associated with autosomal recessive nonsyndromic hearing loss 4.

What condition is associated with FOXI1 p.Pro324= (c.972G>C)?

FOXI1 p.Pro324= (c.972G>C) is associated with autosomal recessive nonsyndromic hearing loss 4 (ClinVar).

How common is FOXI1 p.Pro324= (c.972G>C) in the general population?

FOXI1 p.Pro324= (c.972G>C) is low-frequency (popmax 1.92%, nfe) (gnomAD).

FOXI1 p.Pro324=

c.972G>C · rs56128152 · VCV352710

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.92%, nfe)

Conditions

autosomal recessive nonsyndromic hearing loss 4

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 -8.7	GERP -2.8
Overall
CADD	0.11	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.92% European (non-Finnish) · 22,459/1,172,412 alleles

Filtering AF 1.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.89%

Overall 1.62% 25,994/1,602,972 alleles · low-frequency exomes 24,165/1,450,698 · genomes 1,829/152,274 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.27%	44
European (non-Finnish)grpmax	1.92%	52
Remaining individualsnot grpmax-eligible	1.34%	75
South Asian	0.583%	172
Admixed American	0.571%	175
Ashkenazi Jewishnot grpmax-eligible	0.555%	180
African / African-American	0.301%	333
Middle Eastern	0.183%	546

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: FOXI1
Protein: p.Pro324=
Coding: c.972G>C
MANE Select: NM_012188
dbSNP: rs56128152
Type: single nucleotide variant
Location: chr5:170108446 (GRCh38)
Gene constraint: LOEUF 1.061 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.03

Full FOXI1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive nonsyndromic hearing loss 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FOXI1 p.Pro324Leu Uncertain significance ★ ⚠ same residue
FOXI1 c.-18G>A Uncertain significance ★★ same condition
FOXI1 p.Ala255Thr Uncertain significance ★★ ⚠ same condition
FOXI1 p.Ala338Val Uncertain significance ★★ ⚠ same condition
FOXI1 p.Arg213Cys Uncertain significance ★★ ⚠ same condition
FOXI1 p.Arg267Gln Uncertain significance ★★ ⚠ same condition
FOXI1 p.Asn344Asp Uncertain significance ★★ ⚠ same condition
FOXI1 p.Asn66Lys 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/foxi1-p-pro324 (accessed [today's date]).

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