Is SLC26A5 p.Ala726Val (c.2177C>T) pathogenic?

SLC26A5 p.Ala726Val (c.2177C>T) is classified Conflicting classifications of pathogenicity in SLC26A5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-09). AlphaMissense: likely benign (0.0736); Rare (popmax 0.112%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SLC26A5 p.Ala726Val (c.2177C>T)?

SLC26A5 p.Ala726Val (c.2177C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SLC26A5 p.Ala726Val (c.2177C>T) in the general population?

SLC26A5 p.Ala726Val (c.2177C>T) is rare (popmax 0.112%, nfe) (gnomAD).

What do computational predictors say about SLC26A5 p.Ala726Val (c.2177C>T)?

AlphaMissense predicts likely benign (score 0.0736) — an in-silico prediction, not a clinical call.

SLC26A5 p.Ala726Val

c.2177C>T · rs150726851 · VCV1300471

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0736 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.112%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0736	likely benign
REVEL	0.259	benign-leaning
SaProt	LLR -7.05	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 1	GERP -0.17, phastCons 0.002
Regional constraint	o/e 0.85	unconstrained · MANE · 47 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	6.794	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 0.112% European (non-Finnish) · 1,324/1,180,024 alleles

Filtering AF 0.107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.105%

Overall 0.0845% 1,363/1,613,028 alleles · rare exomes 1,303/1,460,892 · genomes 60/152,136 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.112%	891
Remaining individualsnot grpmax-eligible	0.0353%	2,836
African / African-American	0.02%	4,992
Admixed American	0.00167%	60,000
South Asian	0.0011%	91,008

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: SLC26A5
Protein: p.Ala726Val
Coding: c.2177C>T
MANE Select: NM_198999
dbSNP: rs150726851
Type: single nucleotide variant
Location: chr7:103374457 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.86 · 4 PDB
Residue 726: the 'disordered' region

Full SLC26A5 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

Similar variants

SLC26A5 p.Ala173Thr Uncertain significance ★★ ⚠ same condition
SLC26A5 p.Ala345Thr Uncertain significance ★★ ⚠ same condition
SLC26A5 p.Arg31Thr Uncertain significance ★★ ⚠ same condition
SLC26A5 p.Gln368His Uncertain significance ★★ ⚠ same condition
SLC26A5 p.Gly371Arg Uncertain significance ★★ ⚠ same condition
SLC26A5 p.Gly636Glu Uncertain significance ★★ ⚠ same condition
SLC26A5 p.Ile384Leu Uncertain significance ★★ ⚠ same condition
SLC26A5 p.Ile445Thr 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/slc26a5-p-ala726val (accessed [today's date]).

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