Is SLC4A1 p.Ala726Val (c.2177C>T) pathogenic?

SLC4A1 p.Ala726Val (c.2177C>T) is classified Uncertain significance in SLC4A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: ambiguous (0.5444); Very rare (popmax 0.000508%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SLC4A1 p.Ala726Val (c.2177C>T)?

SLC4A1 p.Ala726Val (c.2177C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SLC4A1 p.Ala726Val (c.2177C>T) in the general population?

SLC4A1 p.Ala726Val (c.2177C>T) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about SLC4A1 p.Ala726Val (c.2177C>T)?

AlphaMissense predicts ambiguous (score 0.5444) — an in-silico prediction, not a clinical call.

SLC4A1 p.Ala726Val

c.2177C>T · VCV4168553

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5444 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5444	ambiguous
REVEL	0.857	moderately pathogenic-leaning
SaProt	LLR -10.41	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 9,991 bp · p 8.9e-14 · regional, not allelic
Overall
CADD	31.0	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 0.000508% European (non-Finnish) · 6/1,180,030 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,988 alleles · very rare exomes 6/1,461,700 · genomes 0/152,288 · 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: SLC4A1
Protein: p.Ala726Val
Coding: c.2177C>T
MANE Select: NM_000342
Type: single nucleotide variant
Location: chr17:44253252 (GRCh38)
Gene constraint: LOEUF 0.407 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.49 · 54 PDB
Residue 726: a β-strand; the '(microbial infection) 5abc region; interaction with p.falciparum (isolate 3d7) msp9' region

Full SLC4A1 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

SLC4A1 p.Ala452Thr Uncertain significance ★★ ⚠ same condition
SLC4A1 p.Ala751Val Uncertain significance ★★ ⚠ same condition
SLC4A1 p.Arg146Gln Uncertain significance ★★ ⚠ same condition
SLC4A1 p.Arg146Trp Uncertain significance ★★ ⚠ same condition
SLC4A1 p.Arg233His Uncertain significance ★★ ⚠ same condition
SLC4A1 p.Arg295Cys Uncertain significance ★★ ⚠ same condition
SLC4A1 p.Arg518His Uncertain significance ★★ ⚠ same condition
SLC4A1 p.Arg782His 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/slc4a1-p-ala726val (accessed [today's date]).

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