Is SLC4A4 p.Pro717Ser (c.2149C>T) pathogenic?

SLC4A4 p.Pro717Ser (c.2149C>T) is classified Uncertain significance in SLC4A4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-26). AlphaMissense: likely benign (0.1494); Very rare (popmax 0.00334%, amr); Associated with Inborn genetic diseases.

What condition is associated with SLC4A4 p.Pro717Ser (c.2149C>T)?

SLC4A4 p.Pro717Ser (c.2149C>T) is associated with Inborn genetic diseases, autosomal recessive proximal renal tubular acidosis (ClinVar).

How common is SLC4A4 p.Pro717Ser (c.2149C>T) in the general population?

SLC4A4 p.Pro717Ser (c.2149C>T) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about SLC4A4 p.Pro717Ser (c.2149C>T)?

AlphaMissense predicts likely benign (score 0.1494) — an in-silico prediction, not a clinical call.

SLC4A4 p.Pro717Ser

c.2149C>T · VCV3590814

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1494 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1494	likely benign
REVEL	0.286	benign-leaning
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 80 kb · p 9e-07 · regional, not allelic
Overall
CADD	22.4	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 0.00334% Admixed American · 2/59,900 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,612,680 alleles · very rare exomes 2/1,460,646 · genomes 2/152,034 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,950
European (non-Finnish)	0.00017%	589,532

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.Pro717Ser
Coding: c.2149C>T
MANE Select: NM_001098484
Type: single nucleotide variant
Location: chr4:71497675 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive proximal renal tubular acidosis

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-pro717ser (accessed [today's date]).

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