Is ASCC1 p.Pro216Leu (c.647C>T) pathogenic?

ASCC1 p.Pro216Leu (c.647C>T) is classified Uncertain significance in ASCC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-16). AlphaMissense: likely benign (0.1668); Very rare (popmax 0.0028%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ASCC1 p.Pro216Leu (c.647C>T)?

ASCC1 p.Pro216Leu (c.647C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ASCC1 p.Pro216Leu (c.647C>T) in the general population?

ASCC1 p.Pro216Leu (c.647C>T) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about ASCC1 p.Pro216Leu (c.647C>T)?

AlphaMissense predicts likely benign (score 0.1668) — an in-silico prediction, not a clinical call.

ASCC1 p.Pro216Leu

c.647C>T · rs752805913 · VCV3130216

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1668 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1668	likely benign
REVEL	0.483	indeterminate
SaProt	LLR -10.32	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 116 kb · p 0.011 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P244L vs ClinVar P216L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0028% European (non-Finnish) · 33/1,179,986 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00175%

Overall 0.00217% 35/1,613,884 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,240
European (non-Finnish)grpmax	0.0028%	35,757

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ASCC1
Protein: p.Pro216Leu
Coding: c.647C>T
MANE Select: NM_001198800
dbSNP: rs752805913
Type: single nucleotide variant
Location: chr10:72152968 (GRCh38)
Gene constraint: LOEUF 1.002 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.70 · 1 PDB

Full ASCC1 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

ASCC1 p.Pro216= Likely benign ★ same residue
ASCC1 p.Ala300Val Uncertain significance ★★ ⚠ same condition
ASCC1 p.Arg14Gln Uncertain significance ★★ ⚠ same condition
ASCC1 p.Arg77Ile Uncertain significance ★★ ⚠ same condition
ASCC1 p.Gln131His Uncertain significance ★★ ⚠ same condition
ASCC1 p.Gln24Arg Uncertain significance ★★ ⚠ same condition
ASCC1 p.Glu102Lys Uncertain significance ★★ ⚠ same condition
ASCC1 p.Gly302Ser 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/ascc1-p-pro216leu (accessed [today's date]).

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