Is UNC13D p.Pro271Ser (c.811C>T) pathogenic?

UNC13D p.Pro271Ser (c.811C>T) is classified Conflicting classifications of pathogenicity in UNC13D (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-25). AlphaMissense: ambiguous (0.3476); Rare (popmax 0.191%, sas); Associated with autoinflammatory syndrome.

What condition is associated with UNC13D p.Pro271Ser (c.811C>T)?

UNC13D p.Pro271Ser (c.811C>T) is associated with autoinflammatory syndrome, familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Pro271Ser (c.811C>T) in the general population?

UNC13D p.Pro271Ser (c.811C>T) is rare (popmax 0.191%, sas) (gnomAD).

What do computational predictors say about UNC13D p.Pro271Ser (c.811C>T)?

AlphaMissense predicts ambiguous (score 0.3476) — an in-silico prediction, not a clinical call.

UNC13D p.Pro271Ser

c.811C>T · rs139564938 · VCV719448

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3476 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.191%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.3476	ambiguous
REVEL	0.188	benign-leaning
SaProt	LLR -5.28	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
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	26.0	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 0.191% South Asian · 174/91,084 alleles

Filtering AF 0.168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.159%

Overall 0.039% 630/1,613,988 alleles · rare exomes 596/1,461,694 · genomes 34/152,294 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.191%	523
Middle Eastern	0.0828%	1,208
European (non-Finnish)	0.0344%	2,906
Remaining individualsnot grpmax-eligible	0.0304%	3,289
Finnishnot grpmax-eligible	0.0266%	3,758
African / African-American	0.00666%	15,009
Admixed American	0.005%	20,007
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Pro271Ser
Coding: c.811C>T
MANE Select: NM_199242
dbSNP: rs139564938
Type: single nucleotide variant
Location: chr17:75840272 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 271: the 'interaction with rab27a' region

Full UNC13D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autoinflammatory syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hemophagocytic lymphohistiocytosis 3

Similar variants

UNC13D c.1055+1G>A Pathogenic/Likely pathogenic ★★ same condition
UNC13D c.118-307G>A Pathogenic ★★ same condition
UNC13D c.118-308C>T Pathogenic/Likely pathogenic ★★ same condition
UNC13D c.1389+1G>A Pathogenic ★★ same condition
UNC13D c.1596+1G>C Pathogenic ★★ same condition
UNC13D c.1727+1G>A Pathogenic/Likely pathogenic ★★ same condition
UNC13D c.1848+1G>A Pathogenic/Likely pathogenic ★★ same condition
UNC13D c.2447+2T>C Likely 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/unc13d-p-pro271ser (accessed [today's date]).

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