Is SLC16A2 p.Ser33Pro (c.97T>C) pathogenic?

SLC16A2 p.Ser33Pro (c.97T>C) is classified Benign/Likely benign in SLC16A2 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0519); Common (popmax 96.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Inborn genetic diseases.

What condition is associated with SLC16A2 p.Ser33Pro (c.97T>C)?

SLC16A2 p.Ser33Pro (c.97T>C) is associated with Inborn genetic diseases, Allan-Herndon-Dudley syndrome, hereditary spastic paraplegia (ClinVar).

What do computational predictors say about SLC16A2 p.Ser33Pro (c.97T>C)?

AlphaMissense predicts likely benign (score 0.0519) — an in-silico prediction, not a clinical call.

SLC16A2 p.Ser33Pro

Q: How common is SLC16A2 p.Ser33Pro (c.97T>C) in the general population?

SLC16A2 p.Ser33Pro (c.97T>C) is common (popmax 96.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.97T>C · rs6647476 · VCV21462

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.0519 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 96.9%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0519	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -2.31	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 0.13	GERP -1.1, phastCons 0.007
Regional constraint	o/e 1.08	unconstrained · MANE · 279 bp · p 0.45 · regional, not allelic
Overall
CADD	7.468	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 96.9% East Asian · 30,768/31,745 alleles

Filtering AF 96% ClinGen BA1/BS1 input FAF95, joint · FAF99 95.6%

Overall 45.5% 529,062/1,162,992 alleles · common exomes 471,969/1,052,988 · genomes 57,093/110,004 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	96.9%	1
African / African-American	69.3%	1
South Asian	63.3%	2
Finnishnot grpmax-eligible	53.3%	2
Remaining individualsnot grpmax-eligible	46.5%	2
European (non-Finnish)	41.4%	2
Admixed American	36.4%	3
Ashkenazi Jewishnot grpmax-eligible	35.2%	3
Middle Eastern	31.6%	3
Amishnot grpmax-eligible	30.7%	3

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: SLC16A2
Protein: p.Ser33Pro
Coding: c.97T>C
MANE Select: NM_006517
dbSNP: rs6647476
Type: single nucleotide variant
Location: chrX:74421734 (GRCh38)
Structure: AlphaFold pLDDT 79.48 · 7 PDB
Residue 33: the 'disordered' region

Full SLC16A2 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: Allan-Herndon-Dudley syndrome hereditary spastic paraplegia

Similar variants

SLC16A2 p.Ser33fs Pathogenic/Likely pathogenic ★★ same residue
SLC16A2 p.Ala150Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
SLC16A2 p.Arg171Ter Pathogenic ★★ same condition
SLC16A2 p.Arg314Ter Pathogenic ★★ same condition
SLC16A2 p.Arg371Cys Pathogenic/Likely pathogenic ★★ same condition
SLC16A2 p.Asp424Asn Likely pathogenic ★★ ⚠ same condition
SLC16A2 p.Gln52Ter Pathogenic ★★ same condition
SLC16A2 p.Glu9Ter Pathogenic ★★ 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/slc16a2-p-ser33pro (accessed [today's date]).

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