Is SLC26A2 p.Ser722Pro (c.2164T>C) pathogenic?

SLC26A2 p.Ser722Pro (c.2164T>C) is classified Uncertain significance in SLC26A2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-07-21). AlphaMissense: likely benign (0.2082); Ultra-rare (popmax 0.0168%, amr); Associated with multiple epiphyseal dysplasia type 4.

What condition is associated with SLC26A2 p.Ser722Pro (c.2164T>C)?

SLC26A2 p.Ser722Pro (c.2164T>C) is associated with multiple epiphyseal dysplasia type 4, diastrophic dysplasia, atelosteogenesis type II (ClinVar).

How common is SLC26A2 p.Ser722Pro (c.2164T>C) in the general population?

SLC26A2 p.Ser722Pro (c.2164T>C) is ultra-rare (popmax 0.0168%, amr) (gnomAD).

How is Multiple epiphyseal dysplasia type 4 inherited?

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

What do computational predictors say about SLC26A2 p.Ser722Pro (c.2164T>C)?

AlphaMissense predicts likely benign (score 0.2082) — an in-silico prediction, not a clinical call.

SLC26A2 p.Ser722Pro

c.2164T>C · rs565149029 · VCV651134

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2082 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

multiple epiphyseal dysplasia type 4

Computational evidence

Protein change
AlphaMissense	0.2082	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -12.90	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -3, phastCons 0.29
Regional constraint	o/e 0.92	unconstrained · MANE · 4,157 bp · p 0.013 · regional, not allelic
Overall
CADD	14.87	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0168% Admixed American · 10/59,448 alleles

Filtering AF 0.00907% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00687%

Overall 0.000931% 15/1,611,580 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0168%	5,945
Remaining individualsnot grpmax-eligible	0.0016%	62,392
African / African-American	0.00134%	74,834
European (non-Finnish)	0.000254%	393,117

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: SLC26A2
Protein: p.Ser722Pro
Coding: c.2164T>C
MANE Select: NM_000112
dbSNP: rs565149029
Type: single nucleotide variant
Location: chr5:149981757 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.97 · 4 PDB
Residue 722: an α-helix

Full SLC26A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

multiple epiphyseal dysplasia type 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: diastrophic dysplasia atelosteogenesis type II achondrogenesis type IB

For Multiple epiphyseal dysplasia type 4 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

SLC26A2 c.700-1G>C Pathogenic/Likely pathogenic ★★ same condition
SLC26A2 c.-26+2T>C Pathogenic ★★ same condition
SLC26A2 p.Ala386Val Pathogenic/Likely pathogenic ★★ same condition
SLC26A2 p.Ala715Val Pathogenic/Likely pathogenic ★★ same condition
SLC26A2 p.Arg178Ter Pathogenic ★★ same condition
SLC26A2 p.Arg279Trp Pathogenic/Likely pathogenic ★★ same condition
SLC26A2 p.Asn425Asp Pathogenic/Likely pathogenic ★★ ⚠ same condition
SLC26A2 p.Cys303Ter Pathogenic/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/slc26a2-p-ser722pro (accessed [today's date]).

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