Is SLC4A4 p.Pro180= (c.540A>G) pathogenic?

SLC4A4 p.Pro180= (c.540A>G) is classified Likely benign in SLC4A4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). Ultra-rare (popmax 0.0147%, nfe).

How common is SLC4A4 p.Pro180= (c.540A>G) in the general population?

SLC4A4 p.Pro180= (c.540A>G) is ultra-rare (popmax 0.0147%, nfe) (gnomAD).

SLC4A4 p.Pro180=

c.540A>G · rs761315715 · VCV2975803

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -2.4
Overall
CADD	2.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0147% European (non-Finnish) · 174/1,180,002 alleles

Filtering AF 0.0129% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0123%

Overall 0.0109% 176/1,613,982 alleles · ultra-rare exomes 174/1,461,788 · genomes 2/152,194 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0147%	6,782
Remaining individualsnot grpmax-eligible	0.0032%	31,240

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.Pro180=
Coding: c.540A>G
MANE Select: NM_001098484
dbSNP: rs761315715
Type: single nucleotide variant
Location: chr4:71350062 (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

Similar variants

SLC4A4 c.1208+4A>C Uncertain significance ★★ same type
SLC4A4 c.1322+5C>T Uncertain significance ★★ same type
SLC4A4 c.*26G>T Uncertain significance ★★ same type
SLC4A4 p.Ala454Thr Uncertain significance ★★ ⚠ same type
SLC4A4 p.Ala454Val Uncertain significance ★★ ⚠ same type
SLC4A4 p.Ala667Thr Uncertain significance ★★ ⚠ same type
SLC4A4 p.Ala744Val Uncertain significance ★★ ⚠ same type
SLC4A4 p.Ala817Thr Uncertain significance ★★ ⚠ same type

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-pro180 (accessed [today's date]).

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