Is UNC13D p.Val91Met (c.271G>A) pathogenic?

UNC13D p.Val91Met (c.271G>A) is classified Conflicting classifications of pathogenicity in UNC13D (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-11-18). AlphaMissense: likely benign (0.0696); Very rare (popmax 0.00954%, eas); Associated with UNC13D-related disorder.

What condition is associated with UNC13D p.Val91Met (c.271G>A)?

UNC13D p.Val91Met (c.271G>A) is associated with UNC13D-related disorder, familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Val91Met (c.271G>A) in the general population?

UNC13D p.Val91Met (c.271G>A) is very rare (popmax 0.00954%, eas) (gnomAD).

What do computational predictors say about UNC13D p.Val91Met (c.271G>A)?

AlphaMissense predicts likely benign (score 0.0696) — an in-silico prediction, not a clinical call.

UNC13D p.Val91Met

c.271G>A · rs374308904 · VCV235323

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0696 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00954%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

UNC13D-related disorder

Computational evidence

Protein change
AlphaMissense	0.0696	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -8.46	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 -3.7
Regional constraint	o/e 0.90	unconstrained · MANE · 7,978 bp · p 0.017 · regional, not allelic
Overall
CADD	0.036	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 0.00954% East Asian · 3/31,444 alleles

Filtering AF 0.00373% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00173% 24/1,387,678 alleles · very rare exomes 21/1,245,298 · genomes 3/142,380 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00954%	10,481
Admixed American	0.00951%	10,519
African / African-American	0.00148%	67,356
European (non-Finnish)	0.00136%	73,740
South Asian	0.00114%	87,918

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.Val91Met
Coding: c.271G>A
MANE Select: NM_199242
dbSNP: rs374308904
Type: single nucleotide variant
Location: chr17:75843064 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB

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

Disease context

UNC13D-related disorder

Also linked: familial hemophagocytic lymphohistiocytosis 3

Similar variants

UNC13D p.Val91= Conflicting classifications of pathogenicity ★ same residue
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

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-val91met (accessed [today's date]).

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