Is SELP p.Pro216Ser (c.646C>T) pathogenic?

SELP p.Pro216Ser (c.646C>T) is classified Uncertain significance in SELP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-16). AlphaMissense: likely benign (0.156); Very rare (popmax 8.48e-05%, nfe).

How common is SELP p.Pro216Ser (c.646C>T) in the general population?

SELP p.Pro216Ser (c.646C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SELP p.Pro216Ser (c.646C>T)?

AlphaMissense predicts likely benign (score 0.156) — an in-silico prediction, not a clinical call.

SELP p.Pro216Ser

c.646C>T · VCV3952044

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.156 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.156	likely benign
REVEL	0.413	indeterminate
SaProt	LLR -10.73	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 40 kb · p 0.88 · regional, not allelic
Overall
CADD	23.9	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 8.48e-05% European (non-Finnish) · 1/1,179,732 alleles

Overall 6.2e-05% 1/1,613,668 alleles · very rare exomes 1/1,461,352 · genomes 0/152,316 · 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: SELP
Protein: p.Pro216Ser
Coding: c.646C>T
MANE Select: NM_003005
Type: single nucleotide variant
Location: chr1:169613058 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.27 · 5 PDB
Residue 216: the sushi 1 domain

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

Similar variants

SELP p.Asn128= Benign ★★ same type
SELP p.Asn673Ser Benign ★★ same type
SELP p.Ser619Ala Benign ★★ same type
SELP p.Thr274Ile Benign ★★ same type
SELP p.Thr767= Benign ★★ same type
SELP p.Ala246Val Uncertain significance ★ ⚠ same type
SELP p.Ala329Thr Uncertain significance ★ ⚠ same type
SELP p.Ala405Gly 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/selp-p-pro216ser (accessed [today's date]).

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