Is SLC19A1 p.Asp56His (c.166G>C) pathogenic?

SLC19A1 p.Asp56His (c.166G>C) is classified Benign/Likely benign in SLC19A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-18). AlphaMissense: likely benign (0.1236); Rare (popmax 0.627%, afr).

How common is SLC19A1 p.Asp56His (c.166G>C) in the general population?

SLC19A1 p.Asp56His (c.166G>C) is rare (popmax 0.627%, afr) (gnomAD).

What do computational predictors say about SLC19A1 p.Asp56His (c.166G>C)?

AlphaMissense predicts likely benign (score 0.1236) — an in-silico prediction, not a clinical call.

SLC19A1 p.Asp56His

c.166G>C · rs146321452 · VCV716648

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1236 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.627%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1236	likely benign
REVEL	0.176	moderately benign-leaning
SaProt	LLR -8.06	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 -1.1	GERP -2.8
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.89 · regional, not allelic
Overall
CADD	15.53	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 0.627% African / African-American · 411/65,572 alleles

Filtering AF 0.577% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.557%

Overall 0.0399% 569/1,425,650 alleles · rare exomes 308/1,284,236 · genomes 261/141,414 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.627%	160
Middle Eastern	0.118%	849
Admixed American	0.0896%	1,116
Remaining individualsnot grpmax-eligible	0.0656%	1,526
European (non-Finnish)	0.00691%	14,465

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: SLC19A1
Protein: p.Asp56His
Coding: c.166G>C
MANE Select: NM_194255
dbSNP: rs146321452
Type: single nucleotide variant
Location: chr21:45537794 (GRCh38)
Gene constraint: LOEUF 1.585 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.30 · 19 PDB
Residue 56: a turn

Full SLC19A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SLC19A1 p.Asp56Asn Uncertain significance ★ ⚠ same residue
COL18A1 p.Arg1081Ter Pathogenic/Likely pathogenic ★★ same type
COL18A1 p.Arg915Ter Pathogenic/Likely pathogenic ★★ same type
RFC1 p.Arg383Ter Pathogenic/Likely pathogenic ★★ same type
COL18A1 c.*30G>A Uncertain significance ★★ same type
COL18A1 p.Ala1089Thr Uncertain significance ★★ ⚠ same type
COL18A1 p.Ala1254Val Uncertain significance ★★ ⚠ same type
COL18A1 p.Arg1081Gln 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/slc19a1-p-asp56his (accessed [today's date]).

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