Is LOXHD1 p.Phe2175Ser (c.6524T>C) pathogenic?

LOXHD1 p.Phe2175Ser (c.6524T>C) is classified Conflicting classifications of pathogenicity in LOXHD1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-11-29). AlphaMissense: likely benign (0.1303); Rare (popmax 0.112%, afr); Associated with Inborn genetic diseases.

What condition is associated with LOXHD1 p.Phe2175Ser (c.6524T>C)?

LOXHD1 p.Phe2175Ser (c.6524T>C) is associated with Inborn genetic diseases, autosomal recessive nonsyndromic hearing loss 77 (ClinVar).

How common is LOXHD1 p.Phe2175Ser (c.6524T>C) in the general population?

LOXHD1 p.Phe2175Ser (c.6524T>C) is rare (popmax 0.112%, afr) (gnomAD).

What do computational predictors say about LOXHD1 p.Phe2175Ser (c.6524T>C)?

AlphaMissense predicts likely benign (score 0.1303) — an in-silico prediction, not a clinical call.

LOXHD1 p.Phe2175Ser

c.6524T>C · rs546735322 · VCV228836

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1303 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.112%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1303	likely benign
REVEL	0.276	benign-leaning
SaProt	LLR -8.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 180 kb · p 0.45 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F1969S vs ClinVar F2175S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.112% African / African-American · 82/73,182 alleles

Filtering AF 0.0925% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0852%

Overall 0.0067% 104/1,551,862 alleles · rare exomes 45/1,399,510 · genomes 59/152,352 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.112%	892
Admixed American	0.0176%	5,668
Remaining individualsnot grpmax-eligible	0.0166%	6,014
European (non-Finnish)	0.000262%	382,343

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: LOXHD1
Protein: p.Phe2175Ser
Coding: c.6524T>C
MANE Select: NM_001384474
dbSNP: rs546735322
Type: single nucleotide variant
Location: chr18:46477770 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.00
Residue 1969 UniProt numbering: the plat 15 domain

Full LOXHD1 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

Also linked: autosomal recessive nonsyndromic hearing loss 77

Similar variants

LOXHD1 p.Phe2175= Likely benign ★ same residue
LOXHD1 c.130+1G>A Likely pathogenic ★★ same condition
LOXHD1 c.2244+1G>A Likely pathogenic ★★ same condition
LOXHD1 c.2437+1G>A Likely pathogenic ★★ same condition
LOXHD1 c.246-1G>A Pathogenic/Likely pathogenic ★★ same condition
LOXHD1 c.246-1G>T Pathogenic/Likely pathogenic ★★ same condition
LOXHD1 c.246-2A>G Pathogenic/Likely pathogenic ★★ same condition
LOXHD1 c.2598+1G>A Likely pathogenic ★★ 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/loxhd1-p-phe2175ser (accessed [today's date]).

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