Is UNC13D p.Ser212Phe (c.635C>T) pathogenic?

UNC13D p.Ser212Phe (c.635C>T) is classified Uncertain significance in UNC13D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: ambiguous (0.3892); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with UNC13D p.Ser212Phe (c.635C>T)?

UNC13D p.Ser212Phe (c.635C>T) is associated with Inborn genetic diseases (ClinVar).

How common is UNC13D p.Ser212Phe (c.635C>T) in the general population?

UNC13D p.Ser212Phe (c.635C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about UNC13D p.Ser212Phe (c.635C>T)?

AlphaMissense predicts ambiguous (score 0.3892) — an in-silico prediction, not a clinical call.

UNC13D p.Ser212Phe

c.635C>T · VCV4634102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3892 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3892	ambiguous
REVEL	0.415	indeterminate
SaProt	LLR -10.49	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 7,978 bp · p 0.017 · regional, not allelic
Overall
CADD	27.6	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 0.000339% European (non-Finnish) · 4/1,179,944 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,950 alleles · very rare exomes 4/1,461,648 · genomes 0/152,302 · 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: UNC13D
Protein: p.Ser212Phe
Coding: c.635C>T
MANE Select: NM_199242
Type: single nucleotide variant
Location: chr17:75840810 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 212: the c2 1 domain

Full UNC13D 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

UNC13D p.Ser212Ala Uncertain significance ★★ ⚠ same residue
UNC13D p.Ala1048Thr Uncertain significance ★★ ⚠ same condition
UNC13D p.Ala1085Val Uncertain significance ★★ ⚠ same condition
UNC13D p.Ala339Thr Uncertain significance ★★ ⚠ same condition
UNC13D p.Ala581Ser Uncertain significance ★★ ⚠ same condition
UNC13D p.Ala604Val Uncertain significance ★★ same condition
UNC13D p.Ala638Val Uncertain significance ★★ ⚠ same condition
UNC13D p.Ala695Thr 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/unc13d-p-ser212phe (accessed [today's date]).

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