Is SLC4A4 p.Pro87Ser (c.259C>T) pathogenic?

SLC4A4 p.Pro87Ser (c.259C>T) is classified Uncertain significance in SLC4A4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-24). AlphaMissense: likely benign (0.3382); Very rare (popmax 8.47e-05%, nfe); Associated with autosomal recessive proximal renal tubular acidosis.

What condition is associated with SLC4A4 p.Pro87Ser (c.259C>T)?

SLC4A4 p.Pro87Ser (c.259C>T) is associated with autosomal recessive proximal renal tubular acidosis (ClinVar).

How common is SLC4A4 p.Pro87Ser (c.259C>T) in the general population?

SLC4A4 p.Pro87Ser (c.259C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Proximal renal tubular acidosis inherited?

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

What do computational predictors say about SLC4A4 p.Pro87Ser (c.259C>T)?

AlphaMissense predicts likely benign (score 0.3382) — an in-silico prediction, not a clinical call.

SLC4A4 p.Pro87Ser

c.259C>T · VCV3590763

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3382 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autosomal recessive proximal renal tubular acidosis

Computational evidence

Protein change
AlphaMissense	0.3382	likely benign
REVEL	0.461	indeterminate
SaProt	LLR -8.24	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 103 kb · p 0.0028 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,992 alleles

Overall 6.2e-05% 1/1,614,126 alleles · very rare exomes 1/1,461,850 · genomes 0/152,276 · joint denominator

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: SLC4A4
Protein: p.Pro87Ser
Coding: c.259C>T
MANE Select: NM_001098484
Type: single nucleotide variant
Location: chr4:71339375 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.77 · 1 PDB

Full SLC4A4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive proximal renal tubular acidosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Proximal renal tubular acidosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: All ages

Similar variants

SLC4A4 c.1208+4A>C Uncertain significance ★★ same condition
SLC4A4 c.1322+5C>T Uncertain significance ★★ same condition
SLC4A4 c.*26G>T Uncertain significance ★★ same condition
SLC4A4 p.Ala454Thr Uncertain significance ★★ ⚠ same condition
SLC4A4 p.Ala454Val Uncertain significance ★★ ⚠ same condition
SLC4A4 p.Ala667Thr Uncertain significance ★★ ⚠ same condition
SLC4A4 p.Ala744Val Uncertain significance ★★ ⚠ same condition
SLC4A4 p.Ala817Thr 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/slc4a4-p-pro87ser (accessed [today's date]).

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